COMPOUNDS AND METHODS OF TREATING HYPERTENSION

Abstract

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. The compounds may bind to and are adrenergic receptor α2B antagonists. The compounds may also bind to and antagonize adrenergic receptor α2B. The compounds may find use in therapy, e.g., to (i) reduce blood pressure and/or (ii) promote renal blood flow and/or (iii) decrease or inhibit sodium reabsorption. The compounds may also be used to treat diseases or conditions that are, or are expected to be, responsive to a decrease in blood pressure. Use of the compounds to treat cardiovascular and renal disorders is particularly described.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 61/444,616 filed Feb. 18, 2011, U.S. Provisional Patent Application No. 61/444,553 filed Feb. 18, 2011, and U.S. Provisional Patent Application No. 61/444,569 filed Feb. 18, 2011, the disclosures of each of which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Hypertension is a serious condition that can damage vital organs, such as the heart and kidneys, and other parts of the body, such as the central nervous system. Individuals who have hypertension may have, or be at risk of developing, dangerous diseases such as coronary heart disease and kidney failure. Hypertension, which is the leading modifiable risk factor for cardiovascular disease mortality, causes more than 7 million deaths every year worldwide.

Hypertension is the most common chronic medical condition in developed countries as well as the most common indication for physician visits and prescription medication use. Hypertension affects more than 50 million individuals in the United States and over one billion individuals worldwide, and overall prevalence may continue to increase with the advancing age of the population.

Unfortunately, despite the importance of blood pressure control and the availability of multiple classes of antihypertensive agents, the treatment of hypertension remains suboptimal. Data from the most recent National Health and Nutrition Examination Survey demonstrate that only 34% of patients with hypertension have blood pressures at their therapeutic goal. Additionally, it was shown that the majority of patients with hypertension will require two or more antihypertensive agents to achieve their goal blood pressure. Even with optimal compliance with multiple antihypertensive agents of different classes, a significant fraction of patients will not be able to achieve their goal blood pressure. The overall prevalence of resistant hypertension, defined as elevated blood pressure in spite of the use of three or more antihypertensive agents, is unknown, but small studies suggest that it ranges from 5%-16% in primary care settings to greater than 50% in nephrology clinics. Given data suggesting that increasing age and obesity are important risk factors for the development of resistant hypertension, it is expected that the overall prevalence of this condition is likely to increase due to demographic changes in the population.

Systolic blood pressure tends to increase with age and systolic hypertension is an important health issue, prominent in the elderly (Duprez, Am. J. Med. 121:179-184 (2008)). It has been suggested that this occurs as large vessels such as the aorta lose their elasticity with age and is less able to buffer the pulsative nature of cardiac output. There exists a need for a treatment for patients in such clinical setting, for example, patients with systolic hypertension accompanied with low diastolic pressure (Franklin et al. J. Hypertension 29:1101-1108 (2011).

Metabolic syndrome is a cluster of disorders including obesity, hypertension, hypertrigleridemia, hypercholesterolemia and elevated blood sugar. Individuals with this spectrum of disorders are at increased risk of diabetes, heart disease and stroke. Agents capable of treating more than one of these disorders are desirable.

Hypertensive emergencies are defined as severe elevations in blood pressure associated with resultant organ damage (i.e. pulmonary edema, renal impairment, visual impairment, intracranial hemorrhage, or encephalopathy). The treatment of hypertensive emergencies involves aggressive and controlled blood pressure lowering in a highly monitored intensive care setting using intravenous blood pressure lowering agents. Therapeutic agents and method of treatment is needed to gradually lower blood pressure and minimize damage of end organs such as the brain, kidney, heart, and eye.

The frequency of chronic kidney disease also continues to increase worldwide as does the prevalence of end-stage renal disease. Although chronic kidney disease is often caused by hypertension, other factors such as a decrease in renal blood flow and increase in sodium retention or reabsorption can lead to renal diseases. Increased age and diabetes can also contribute to renal disease. Especially the elderly, which are a growing segment of the world population, are at increased risk for renal disease. The presence of chronic kidney disease is also associated with a large increase in cardiovascular morbidity and mortality. Consequently, the identification and reduction of chronic kidney disease has become a vital public health priority.

Thus, there remains a need for new and useful agents that are capable of (i) reducing an individual's blood pressure and/or (ii) promoting renal blood flow and/or (iii) inhibiting or decreasing sodium reabsorption.

BRIEF SUMMARY OF THE INVENTION

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. Compositions and kits comprising the compounds are also provided, as are methods of using and making the compounds. Compounds provided herein may find use in treating a disease or condition that is, or is believed to be responsive to any one or more of: (i) a decrease in blood pressure; (ii) an increase in renal blood flow and (iii) a decrease or inhibition of sodium reabsorption. In one aspect, compounds provided herein are selective adrenergic receptor α_2B antagonists that may find use in treating a disease or condition that is, or is believed to be responsive to any one or more of: (i) a decrease in blood pressure; (ii) an increase in renal blood flow and (iii) a decrease or inhibition of sodium reabsorption. Compounds provided may also find use in treating diseases and/or conditions such as hypertension, congestive heart failure or a renal disease or condition.

In another aspect, compounds that promote mitochondrial health and cellular viability are also described. The compounds provided herein are selective adrenergic receptor α_2B antagonists that may find use in treating a disease or condition that is associated with dysfunction of mitochondria in a renal or cardiac cell. Compounds provided may also find use in treating diseases and/or conditions selected from the group consisting of acute renal failure, chronic renal failure, coronary ischemia, acute congestive heart failure, chronic congestive heart failure, coronary artery disease, sleep apnea, respiratory distress, hypertension, and peripheral vascular disease.

In one aspect, the present invention provides methods of lowering blood pressure in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof; and wherein the formulae (A1) to (D4) are as described herein. In one embodiment, the method reduces systolic blood pressure of the individual. In another embodiment, the method reduces diastolic blood pressure of the individual. In another embodiment, the method reduces (i) mean arterial blood pressure, or (ii) pulse pressure, of the individual. In another embodiment, the method does not substantially increase heart rate of the individual. In another embodiment, the individual has one or more risk factors for developing high blood pressure. In another embodiment, the individual has high blood pressure.

In another aspect, the present invention provides methods of (i) increasing renal blood flow, and/or (ii) decreasing sodium reabsorption, in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof. In one embodiment, the method results in increase in renal blood flow. In another embodiment, the method results in decrease in sodium reabsorption. In another embodiment, the method results in increase in urine sodium content and/or increase in urine volume. In another embodiment, the method results in any one or more of: (i) reducing edema, (ii) reducing elevated blood urea nitrogen to creatinine (BUN/Cr) ratio, and (iii) decreasing creatinine levels. In another embodiment, the individual has or is at risk of developing acute or chronic congestive heart failure, acute decompensated congestive heart failure, acute or chronic renal failure, or acute or chronic renal failure due to renal insufficiency.

In another aspect, the present invention provides methods of treating a disease or condition that is responsive to any one or more of: (i) a decrease in blood pressure; (ii) an increase in renal blood flow; and (iii) a decrease of sodium reabsorption, comprising administering to an individual in need thereof an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof. In one embodiment, the disease or condition is hypertension. In another embodiment, the disease or condition is treatment-resistant hypertension. In another embodiment, the disease or condition is hypertensive emergency. In another embodiment, the disease or condition is a cardiac or renal disease or condition. In another embodiment, the compound is an adrenergic receptor α_2B antagonist. In another embodiment, the compound is also an adrenergic receptor α_1B antagonist. In another embodiment, the compound is also an adrenergic receptor α_1D antagonist.

In a further aspect, the present invention provides a kit comprising (i) a compound of formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof, and (ii) instructions for use according to the methods of the invention

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless clearly indicated otherwise, the terms “a,” “an,” and the like, refer to one or more.

It is also understood and clearly conveyed by this disclosure that reference to “the compound” or “a compound” includes and refers to any compounds (e.g., selective adrenergic receptor α_2B antagonists) or pharmaceutically acceptable salt or other form thereof as described herein.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a human. The invention may find use in both human medicine and in the veterinary context.

As used herein, an “at risk” individual is an individual who is at risk of developing a disease or condition. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).

As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, including clinical results.

As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

As used herein, the term “effective amount” intends such amount of a compound of the invention which should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound which may be in a pharmaceutically acceptable carrier.

As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

The term “excipient” as used herein includes an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound detailed herein, or a pharmaceutically acceptable salt thereof, as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

An inverse agonist is a compound that binds to a receptor and inhibits the activity of the receptor in the absence of an agonist. An inverse agonist requires that the receptor have some constitutive basal activity in the absence of an agonist. While an agonist increases activity of the receptor over basal level an inverse agonist reduces receptor activity below basal level.

“Alkyl” refers to and includes saturated linear, branched, or cyclic univalent hydrocarbon structures and combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C₁-C₈ alkyl”). When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈ cycloalkyl”). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

“Alkylene” refers to the same residues as alkyl, but having bivalency. Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms. Examples of alkenyl include but are not limited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethyl group of the latter example can be attached to the cyclohexenyl moiety at any available position on the ring. Cycloalkenyl is a subset of alkenyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as norbornenyl. A more preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈ cycloalkenyl”). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and preferably having from 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the rings can be aryl or heteroaryl. A heterocycle having more than one ring where at least one ring is aromatic may be connected to the parent structure at either a non-aromatic ring position or at an aromatic ring position. In one variation, a heterocycle having more than one ring where at least one ring is aromatic is connected to the parent structure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. In one variation, a substituted heterocycle is a heterocycle substituted with an additional ring, wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclic group having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. Preferably, an aralkyl is connected to the parent structure via the alkyl moiety. In one variation, an aralkyl is a fused ring system where at least one cycloalkyl moiety is fused with at least one aryl moiety. A “substituted aralkyl” refers to a residue in which an aryl moiety is attached to a substituted alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. When an aralkyl is connected to the parent structure via the alkyl moiety, it may also be referred to as an “alkaryl”. More particular alkaryl groups are those having 1 to 3 carbon atoms in the alkyl moiety (a “C₁-C₃ alkaryl”).

“Alkoxy” refers to the group alkyl-O—, which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxy refers to the group “alkynyl-O—”. “Substituted alkoxy” refers to the group substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_aR_b, where either (a) each R_a and R_b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, provided that both R_a and R_b groups are not H; or (b) R_a and R_b are joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_aR_b where R_a and R_b are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic or R_a and R_b groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring.

“Aminoacyl” refers to the group —NR_aC(O)R_b where each R_a and R_b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_a is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substituted alkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl, —NRSO₂-substituted alkynyl, —NRSO₂-cycloalkyl, —NRSO₂-substituted cycloalkyl, —NRSO₂-aryl, —NRSO₂-substituted aryl, —NRSO₂-heteroaryl, —NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic, and —NRSO₂-substituted heterocyclic, where R is H or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl, —SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl, —SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl, —SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substituted heteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic, where R is H or alkyl, or —SO₂NR₂, where the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substituted alkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-aralkyl, —SO₂-substituted aralkyl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substituted heterocyclic.

“Aminocarbonylalkoxy” refers to the group —NR_aC(O)OR_b where each R_a and R_b group is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Carbonylalkylenealkoxy” refers to the group —C(O)—(CH₂)_n—OR where R is a substituted or unsubstituted alkyl and n is an integer from 1 to 100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each H is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_aR_b where R_a and R_b are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or the R_a and R_b groups can be joined together with the nitrogen atom to form a heterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that are attached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹ and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that are attached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹ and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

Receptor Binding Profile

In some embodiments, compounds that bind to and are antagonists of the adrenergic receptor α_2B, but which are not antagonists of the adrenergic receptor α_2A, and pharmaceutically acceptable salts thereof, are provided. The compounds may find use in therapy for decreasing blood pressure in an individual and in treating diseases or conditions which are responsive to (i) a decrease in blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption or sodium retention. Thus, an individual who has a disease or condition that is responsive to (i) a decrease in blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption or sodium retention will experience one or more beneficial or desirable results upon administration of a compound provided herein, or pharmaceutically acceptable salt thereof. In one aspect, the beneficial or desirable result is a reduction in the individual's mean arterial blood pressure for a period of time following administration of the compound or pharmaceutically acceptable salt thereof. In another aspect, the beneficial or desirable result is a reduction in the individual's systolic blood pressure for a period of time following administration of the compound or pharmaceutically acceptable salt thereof. In a further aspect, the beneficial or desirable result is an increase in renal blood flow (e.g., by altering the vascular tone of renal efferent and afferent arterioles) for a period of time following administration of the compound or pharmaceutically acceptable salt thereof. In another aspect, the beneficial or desirable result is a decrease or inhibition in sodium reabsorption (e.g., thereby exerting a natriuretic and diuretic effect) for a period of time following administration of the compound or pharmaceutically acceptable salt thereof. In another aspect, the beneficial or desirable result is an increase in urine sodium and/or urine volume for a period of time following administration of the compound or pharmaceutically acceptable salt thereof. In one variation, the compounds may find use in therapy in treating diseases or conditions which are responsive to (i) a decrease in blood pressure and (ii) an increase in renal blood flow. In one variation, the compounds my find use in therapy in treating diseases or conditions which are responsive to (i) a decrease in blood pressure and (ii) a decrease or inhibition of sodium reabsorption. In one variation, the compounds may find use in treating diseases or conditions which are responsive to (i) an increase in renal blood flow and (ii) a decrease or inhibition of sodium reabsorption. In one variation, the compounds may find use in therapy in treating diseases or conditions which are responsive to (i) a decrease in blood pressure and (ii) an increase in renal blood flow and (iii) a decrease or inhibition of sodium reabsorption.

Compounds that bind to and are antagonists of the adrenergic receptor α_2B should reduce an individual's blood pressure. However, compounds that antagonize the adrenergic receptor α_2A in some instances may actually increase an individual's blood pressure. Thus, compounds that antagonize the adrenergic receptor α_2B but do not antagonize the adrenergic receptor α_2A (compounds referred to herein as “selective adrenergic receptor α_2B antagonists”) are desirable agents in therapy. Selective adrenergic receptor α_2B antagonists find further use in therapy of cardiovascular and renal indications. The selective adrenergic receptor α_2B antagonists provided herein (i) bind to and are antagonists of the adrenergic receptor α_2B, and (ii) are not antagonists of the adrenergic receptor α_2A.

The selective adrenergic receptor α_2B antagonists may in some variations also bind to and be agonists of the adrenergic receptor α_2A. The selective adrenergic receptor α_2B antagonists may also be used in conjunction with other agents that are agonists of the adrenergic receptor α_2A.

The selective adrenergic receptor α_2B antagonists may in some variations also bind to and be antagonists of the adrenergic receptor α_1B. The selective adrenergic receptor α_2B antagonists may also be used in conjunction with other agents that are antagonists of the adrenergic receptor α_1B.

The selective adrenergic receptor α_2B antagonists may in some variations also bind to and be antagonists of the adrenergic receptor α_1D. The selective adrenergic receptor α_2B antagonists may also be used in conjunction with other agents that are antagonists of the adrenergic receptor α_1D.

The selective adrenergic receptor α_2B antagonists may in some variations both (i) bind to and be agonists of the adrenergic receptor α_2A and (ii) bind to and be antagonists of the adrenergic receptor α_1B and/or α_1D.

In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A. In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, and (ii) equal to or less than about any one of 30%, 25%, 20%, 15%, 10%, or 5%, or between about 0% and about 30%, between about 10% and about 30%, or between about 20% and about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A. In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A. In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_2B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B, and (ii) equal to or less than about any one of 30%, 25%, 20%, 15%, 10%, or 5%, or between about 0% and about 30%, between about 10% and about 30%, or between about 20% and about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A. It is understood and clearly conveyed herein that a selective adrenergic receptor α_2B antagonist can exhibit any of the adrenergic receptor α_2B binding profiles described herein in combination with any of the adrenergic receptor α_2A binding profiles described herein, as if each and every combination were listed separately. For example, a selective adrenergic receptor α_2B antagonist may exhibit (i) equal to or greater than about 65% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, and (ii) equal to or less than about 25% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A.

In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.03 μM and absence of antagonist activity to adrenergic receptor α_2A. In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, and (ii) equal to or less than about any one of 30%, 25%, 20%, 15%, 10%, or 5%, or between about 0% and about 30%, between about 10% and about 30%, or between about 20% and about 30% inhibition of α_2A ligand binding at 0.03 μM and absence of antagonist activity to adrenergic receptor α_2A. In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.03 μM and absence of antagonist activity to adrenergic receptor α_2A. In one variation, a selective adrenergic receptor α_2B antagonist exhibits (i) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and about 90%, between about 70% and about 90%, or between about 80% and about 100% inhibition of α_2B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B, and (ii) equal to or less than about any one of 30%, 25%, 20%, 15%, 10%, or 5%, or between about 0% and about 30%, between about 10% and about 30%, or between about 20% and about 30% inhibition of α_2A ligand binding at 0.03 μM and absence of antagonist activity to adrenergic receptor α_2A. It is understood and clearly conveyed herein that a selective adrenergic receptor α_2B antagonist can exhibit any of the adrenergic receptor α_2B binding profiles described herein in combination with any of the adrenergic receptor α_2A binding profiles described herein, as if each and every combination were listed separately. For example, a selective adrenergic receptor α_2B antagonist may exhibit (i) equal to or greater than about 65% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, and (ii) equal to or less than about 25% inhibition of α_2A ligand binding at 0.03 μM and absence of antagonist activity to adrenergic receptor α_2A.

In another variation, a selective adrenergic receptor α_2B antagonist has a Ki ratio of α_2A to α_2B that is greater than about any one of 5 or 15 or 50. Ki is the binding affinity from the Cheng-Prusoff equation: Ki=IC₅₀/(1+[S]/Kd), wherein [S] is the concentration of the radioligand and Kd is dissociation constant (affinity) of the radioligand for the protein (Cheng, Y., Prusoff, W. H., Biochem. Pharmacol. 22:3099-3108, 1973). It is understood that the Ki ratio of α_2A to α_2B may be combined with any binding and/or other activity profile details described herein for selective adrenergic receptor α_2B antagonists the same as if each were specifically and individually listed. For example, in one variation, a selective adrenergic receptor α_2B antagonist may exhibit (i) equal to or greater than about 65% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, and (ii) equal to or less than about 25% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A; and a Ki ratio of α_2A to α_2B that is greater than about any one of 5 or 15 or 50.

The selective adrenergic receptor α_2B antagonists may in some variations also bind to and be antagonists of the adrenergic receptor α_1B. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 60% inhibition of α_1B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1B. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and 90%, between about 70% and 90%, or between about 80% and about 100% inhibition of α_1B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1B. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 60% inhibition of α_1B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 60% inhibition of α_1B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and 90%, between about 70% and 90%, or between about 80% and about 100% inhibition of α_1B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B. It is understood and clearly conveyed herein that a selective adrenergic receptor α_2B antagonist can exhibit any of the adrenergic receptor α_2B binding profiles described herein in combination with any of the adrenergic receptor α_2A binding profiles described herein and any of the adrenergic receptor α_1B binding profiles, as if each and every combination were listed separately. For example, a selective adrenergic receptor α_2B antagonist may exhibit (i) equal to or greater than about 65% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 25% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 65% inhibition of α_1B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1B. The selective adrenergic receptor α_2B antagonists may also be used in conjunction with other agents that antagonize the adrenergic receptor α_1B. Administration in conjunction with another compound includes administration in the same or different composition, either sequentially, simultaneously, or continuously.

The selective adrenergic receptor α_2B antagonists may in some variations also bind to and be antagonists of the adrenergic receptor α_1D. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 60% inhibition of α_1D ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1D. In another variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, (iii) equal to or greater than about 60% inhibition of α_1B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1B and (iv) equal to or greater than about 60% inhibition of α_1D ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1D. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and 90%, between about 70% and 90%, or between about 80% and about 100% inhibition of α_1D and/or α_1B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1D and/or α_1B. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 60% inhibition of α_1B and/or α_1D ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B and/or α_1D. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 60% inhibition of α_1B and/or α_1D ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B and/or α_1D. In one variation, the selective adrenergic receptor α_2B antagonists may exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% and 90%, between about 70% and 90%, or between about 80% and about 100% inhibition of α_1B and/or α_1D ligand binding at 0.1 μM and antagonist activity to adrenergic receptor α_1B and/or α_1D. It is understood and clearly conveyed herein that a selective adrenergic receptor α_2B antagonist can exhibit any of the adrenergic receptor α_2B binding profiles described herein in combination with any of the adrenergic receptor α_2A binding profiles described herein and any of the adrenergic receptor α_1B and/or α_1D binding profiles, as if each and every combination were listed separately. For example, a selective adrenergic receptor α_2B antagonist may exhibit (i) equal to or greater than about 65% inhibition of α_2B ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_2B, (ii) equal to or less than about 25% inhibition of α_2A ligand binding at 0.1 μM and absence of antagonist activity to adrenergic receptor α_2A, and (iii) equal to or greater than about 65% inhibition of α_1D ligand binding at 0.03 μM and antagonist activity to adrenergic receptor α_1D. The selective adrenergic receptor α_2B antagonists may also be used in conjunction with other agents that antagonize the adrenergic receptor α_1D. Administration in conjunction with another compound includes administration in the same or different composition, either sequentially, simultaneously, or continuously.

In some instances, compounds provided herein bind to and are antagonists of adrenergic receptor α_2B and may also be antagonists for the adrenergic receptor α_2A. In such instances, it is preferable that the compound is more potent at inhibiting the adrenergic receptor α_2B compared to the adrenergic receptor α_2A. In one variation, the compound inhibit both the adrenergic receptor α_2B and the adrenergic receptor α_2A, and wherein the compound has limited of no brain bioavailability and so cannot easily activate adrenergic α_2A receptors in the brain. In one variation, the compound inhibit both the adrenergic receptor α_2B and the adrenergic receptor α_2A, and wherein the compound has brain bioavailability. In some other instances, compounds provided herein bind to and are antagonists of adrenergic receptor α_2B and may be inverse agonists for the adrenergic receptor α_2A. In some embodiments, the compound (1) binds to and is an antagonist of adrenergic receptor α_2B, and (2) binds to and is an antagonist and/or inverse agonist of the adrenergic receptor α_2A. In some embodiments, the compound (1) binds to and is an antagonist of adrenergic receptor α_2B, (2) binds to and is an antagonist and/or inverse agonist of the adrenergic receptor α_2A, and (3) binds to and is antagonist of the adrenergic receptor α_1B and/or the adrenergic receptor α_1D. It is understood and clearly conveyed herein that an adrenergic receptor α_2B antagonist can exhibit any of the adrenergic receptor α_2B binding profiles (in terms of % inhibition at a given concentration and/or in terms of K_i) described herein in combination with any of the adrenergic receptor α_1B and/or α_1D binding profiles, as if each and every combination were listed separately.

The binding properties to adrenergic receptors of compounds disclosed herein may be assessed by methods known in the art, such as competitive binding assays. In one variation, compounds are assessed by the binding assays detailed herein. In one variation, inhibition of binding of a ligand to a receptor is measured by the assays described herein. In another variation, inhibition of binding of a ligand is measured in an assay known in the art.

Functional Assay Profile

Antagonist activity to the adrenergic receptor α_2B receptor may be assessed by methods known in the art, such as standard α_2B receptor cell membrane-based or intact cell-based activity assays. For example, the GTPγS binding or Aequorin-based assays may be used. In one variation, the selective adrenergic receptor α_2B antagonists exhibit an IC₅₀ value equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)) in an α_2B antagonist assay. In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2B antagonist assay equal to or less than about 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)) in an α_2B antagonist assay. In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of oxymetazoline corresponding to its EC₈₀ concentration as obtained by assay protocols described herein. In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of oxymetazoline between about 50 nM and about 5000 nM. In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 480 nM oxymetazoline. In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of guanfacine between about 50 nM and about 5000 nM. In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 500 nM guanfacine, which in a particular variation is 504 nM guanfacine.

The absence of antagonist activity to the adrenergic receptor α_2A may be assessed by methods known in the art, such as standard α_2A receptor intact cell-based activity assays. For example, the Aequorin-based assay may be used. It is understood and clearly conveyed that absence of antagonist activity to the adrenergic receptor α_2A intends activity that is sufficiently reduced, but not necessarily eliminated or undetectable, at the adrenergic receptor α_2A. In one variation, a compound will exhibit an undetectable amount of antagonist activity to the adrenergic receptor α_2A. In another variation, a compound will lack antagonist activity to the adrenergic receptor α_2A if it exhibits an IC₅₀ value in an α_2A antagonist assay that is greater than about any one of 50 nM, 100 nM or 200 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of UK14304). In one variation, the adrenergic receptor α_2A exhibits an IC₅₀ value in an α_2A antagonist assay that is greater than about 200 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of UK14304). In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2A antagonist assay greater than about any one of 50 nM, 100 nM or 200 nM at a concentration of UK14304 corresponding to its EC₈₀ concentration as obtained by assay protocols described herein. In one variation, a selective adrenergic receptor α_2B antagonist exhibits an IC₅₀ value in an α_2A antagonist assay greater than about any one of 50 nM, 100 nM or 200 nM at a concentration of UK14304 between about 0.4 nM and about 40 nM. In one variation, a selective adrenergic receptor α_2B antagonists exhibits an IC₅₀ value in an α_2A antagonist assay greater than about any one of 50 nM, 100 nM or 200 nM at a concentration of about 5 nM UK14304, which in a particular variation is 4.57 nM UK14304. Alternatively, a compound that does not bind the α_2A receptor will be neither an agonist nor antagonist of the α_2A receptor.

In some variations, regardless of IC₅₀ values obtained from α_2B and α_2A assays, a compound may nonetheless be a selective adrenergic receptor α_2B antagonist if it exhibits a Ki ratio of α_2A to α_2B that is higher than about any one of 5, 10, or 15. For example, where a compound exhibits an IC₅₀ value between about 50-100 nM in an α_2B antagonist assay at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline) and an IC₅₀ value between about 50 and 100 nM in an α_2A antagonist assay at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of UK14304), the compound is considered, in one variation, a selective adrenergic receptor α_2B antagonist if it exhibits a Ki ratio of α_2A to α_2B higher than about any one of 5, 10, or 15.

Antagonist activity to adrenergic receptor α_1B may be assessed by methods known in the art, such as standard α_1B receptor intact cell-based activity assays, including the Aequorin-based assay. In one variation, a selective adrenergic receptor α_2B antagonist will also antagonize the adrenergic receptor α_1B and exhibit an IC₅₀ value equal to or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline) in an adrenergic receptor α_1B antagonist assay. In one variation, a selective adrenergic receptor α_2B antagonist will also antagonize the adrenergic receptor α_1B and exhibit an IC₅₀ value equal or less than about 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline) in an adrenergic receptor α_1B antagonist assay. In one variation, the selective adrenergic receptor α_2B antagonists exhibit an IC₅₀ value in an α_1B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline corresponding to its EC₈₀ concentration as obtained by assay protocols described herein. In one variation, the selective adrenergic receptor α_2B antagonists exhibit an IC₅₀ value in an α_1B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline between about 2.3 nM and about 230 nM. In one variation, the selective adrenergic receptor α_2B antagonists exhibit an IC₅₀ value in an α_1B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 25 nM cirazoline, which in a particular variation is 23.56 nM cirazoline.

Antagonist activity to adrenergic receptor α_1D may be assessed by methods known in the art, such as standard α_1D receptor intact cell-based activity assays, including the Aequorin-based assay. In one variation, a selective adrenergic receptor α_2B antagonist will also antagonize the adrenergic receptor α_1D and exhibit an IC₅₀ value equal to or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline) in an adrenergic receptor α_1D antagonist assay. In one variation, a selective adrenergic receptor α_2B antagonist will also antagonize the adrenergic receptor α_1D and exhibit an IC₅₀ value equal or less than about 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline) in an adrenergic receptor α_1D antagonist assay. In one variation, the selective adrenergic receptor α_2B antagonists exhibit an IC₅₀ value in an α_1D antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline corresponding to its EC₈₀ concentration as obtained by assay protocols described herein. In one variation, the selective adrenergic receptor α_2B antagonists exhibit an IC₅₀ value in an α_1D antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of cirazoline between about 2.3 nM and about 230 nM. In one variation, the selective adrenergic receptor α_2B antagonists exhibit an IC₅₀ value in an α_1D antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of about 25 nM cirazoline, which in a particular variation is 23.56 nM cirazoline.

In one variation, the selective adrenergic receptor α_2B antagonists exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)), and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and an IC₅₀ value in an α_2A antagonist assay that is greater than about any one of 50 nM, 100 nM or 200 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of UK14304). In some variations, the selective adrenergic receptor α_2B antagonists exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)), and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and an IC₅₀ value in an α_2A antagonist assay that is greater than about any one of 50 nM, 100 nM or 200 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of UK14304), and (iii) equal to or greater than about 60% inhibition of α_1B ligand binding at 0.03 μM and an IC₅₀ value in an α_1B antagonist assay equal or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline). In some variations, the selective adrenergic receptor α_2B antagonists exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)), and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and an IC₅₀ value in an α_2A antagonist assay that is greater than about any one of 50 nM, 100 nM or 200 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of UK14304), and (iii) equal to or greater than about 60% inhibition of α_1D ligand binding at 0.03 μM and an IC₅₀ value in an α_1D antagonist assay equal or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline). In some variations, the selective adrenergic receptor α_2B antagonists exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and an IC₅₀ value in an α_2B antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)), and (ii) equal to or less than about 30% inhibition of α_2A ligand binding at 0.1 μM and an IC₅₀ value in an α_2A antagonist assay that is greater than about any one of 50 nM, 100 nM or 200 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of UK14304), (iii) equal to or greater than about 60% inhibition of α_1B ligand binding at 0.03 μM and an IC₅₀ value in an α_1B antagonist assay equal or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline); and (iv) equal to or greater than about 60% inhibition of α_1D ligand binding at 0.03 μM and an IC₅₀ value in an α_1D antagonist assay equal or less than about any one of 100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of cirazoline).

In another variation, the selective adrenergic receptor α_2B antagonists exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and an IC₅₀ value in an α_2B antagonist assay equal to or less than any about one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)), and (ii) binding to and agonist activity to adrenergic receptor α_2A.

In another variation, the adrenergic receptor α_2B antagonists exhibit (i) equal to or greater than about 60% inhibition of α_2B ligand binding at 0.03 μM and an IC₅₀ value in an α_2B antagonist assay equal to or less than any about one of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)), and (ii) greater than or equal to about 50% inhibition of α_2A ligand binding at 0.1 μM and IC₅₀ value in an adrenergic receptor α_2A antagonist assay equal to or less than about any one of 100 nM, 30 nM or 10 nM at a concentration of UK14304 (for Aequorin assay) corresponding to its EC₈₀ concentration obtained by assay protocols described herein.

It is understood and clearly conveyed herein that compounds provided herein, including selective adrenergic receptor α_2B antagonists provided herein can exhibit any of the binding profiles and any of the antagonist or agonist activity profiles detailed herein, the same as if each and every combination were individually listed. For example, in one variation, the selective adrenergic receptor α_2B antagonists exhibit (i) greater than about 65% inhibition of α_2B ligand binding at 0.03 μM and an IC₅₀ value in an α_2B antagonist assay equal to or less than about 10 nM at a concentration of oxymetazoline corresponding to its EC₈₀ concentration as obtained by assay protocols described herein, and (ii) less than about 25% inhibition of α_2A ligand binding at 0.1 μM and an IC₅₀ value in an α_2A antagonist assay that is greater than 200 nM at a concentration of UK14304 corresponding to its EC₈₀ concentration as obtained by assay protocols described herein, and (iii) equal to or greater than about 60% inhibition of α_1B ligand binding at 0.03 μM and an IC₅₀ value in an α_1B antagonist assay equal or less than 10 nM at a concentration of cirazoline corresponding to its EC₈₀ concentration as obtained by assay protocols described herein. In one aspect, such a compound will also exhibit a Ki ratio of α_2A to α_2B that is greater than about any one of 5 or 15 or 50.

Medical Use

Without being bound by theory, it is believed that the compounds provided herein are capable of (i) reducing blood pressure and/or (ii) promoting renal blood flow and/or (iii) decreasing or inhibiting sodium reabsorption. In some embodiments, the compounds are adrenergic receptor α_2B antagonists (e.g., selective adrenergic receptor α_2B antagonists). In some embodiments, it is believed that the selective adrenergic receptor α_2B antagonists provided herein are capable of (i) reducing blood pressure and/or (ii) promoting renal blood flow and/or (iii) decreasing or inhibiting sodium reabsorption without concomitantly antagonizing the α_2A receptor, which would reduce or potentially eliminate the beneficial blood pressure lowering and renal effects modulated by antagonizing α_2B. Furthermore, the selective adrenergic receptor α_2B antagonists provided herein may be capable of decreasing blood pressure sensitivity to salt, decreasing sodium retention, decreasing vasoconstriction in small arteries and veins, increasing insulin secretion, increasing basal metabolic rate, decreasing platelet aggregation and/or enhancing mitochondrial function. However, in certain cases where the compound has strong antagonist activities against adrenergic receptor α_2B and/or adrenergic receptor α_1B, some antagonist activity against adrenergic receptor α_2A may be tolerated and even beneficial.

Compounds provided herein may be capable of mediating control of the renal function. Adrenergic α_2B receptors are located within the kidney. Regard et al. (Cell 2008; 135:561) have demonstrated that the gene for the adrenergic α_2B receptor is most abundantly expressed in the kidney. Meister et al. (J. Pharmacol. Exp. Therapeutics 1994; 268:1605) have shown by in situ hybridization that expression predominates in the medulla outer stripe with extensions into the cortical S3 segment of the proximal tubules. Adrenergic α_2B receptor antagonists provided herein may be capable of disrupting sodium reabsorption resulting in natriuresis and diuresis. Methods to determine effects of adrenergic α_2B antagonists on renal function in a rabbit model of hypertension have been described by Burke et al. (J Hypertens 29:945-952).

In addition to reducing blood pressure, compounds disclosed herein, including adrenergic α_2B antagonists, are capable of a reduction in blood volume that might result from diueresis and/or the movement of fluid from the vascular space to the extravascular space. Reduction of blood volume results in increase in hematocrit levels which can be measured by methods known in the art, for example by estimation of erythrocyte volume_fraction Characterization of the effect of α_2B antagonists on renal function are determined by measuring urine volume, urine sodium and urine potassium using methods described by Burke et al. (Effects of chronic sympatho-inhibition on renal excretory function in renovascular hypertension Sandra L. Burke, Roger G. Evans and Geoffrey A. Head. Journal of Hypertens 29:945-952 (2011).

The compounds detailed herein are expected to find use in therapy, particularly in cardiac and renal diseases and conditions, in addition to hypertension and other conditions in which a (i) reduction in blood pressure and/or (ii) increase in renal blood flow and/or (iii) decrease in sodium reabsorption would be beneficial. In the methods provided herein, an effective amount of a compound detailed herein is administered to an individual. Methods of using compounds as described herein to (i) reduce blood pressure and/or (ii) promote renal blood flow and/or (iii) decrease or inhibit sodium reabsorption in an individual in need thereof are provided. The compounds may also find use in treating a disease or condition that is, or is expected to be, responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption. The individual may be a human who has been diagnosed with or is suspected of having high blood pressure or a disease or condition that is, or is expected to be, responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption. The individual may be a human who exhibits one or more symptoms associated with high blood pressure or a disease or condition that is, or is expected to be, responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption. The individual may be a human who is genetically or otherwise predisposed to developing high blood pressure or a disease or condition that is, or is expected to be, responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption. In one variation, the compounds may find use in treating metabolic syndrome. In some embodiments, the compounds are adrenergic receptor α_2B antagonists. In one variation, the adrenergic receptor α_2B antagonists are selective adrenergic receptor α_2B antagonists. In one variation, a compound that is an adrenergic receptor α_2B antagonist also showing adrenergic receptor α_2A antagonist and/or inverse agonist activity may find use reducing blood pressure in an individual with hypertension who is also suffering from obesity, type-2 diabetes and/or metabolic syndrome. Thus, provided is a method for lowering blood pressure in hypertensive patients with a disease or condition that is responsive to treatment using an antagonist or inverse agonist of adrenergic receptor α_2A, such as obesity and/or type-2 diabetes and/or metabolic syndrome.

Compounds detailed herein may be used in a method of treating a disease or condition that is responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption. For example, the compounds may find use in treating hypertension, including treatment-resistant hypertension. In some embodiments, the compounds may be used in a method of treating hypertension in an individual not suffering from obesity or type-2 diabetes. In some embodiments, the compounds are adrenergic receptor α_2B antagonists. In some embodiments, the compounds are selective adrenergic receptor α_2B antagonists.

In one aspect, the disease or indication is a cardiac or renal disease or indication for which (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption would be, or would be expected to be, beneficial. Such cardiac indications include, but are not limited to, heart failure, such as compensated heart failure, decompensated heart failure, acute decompensated congestive heart failure and chronic congestive heart failure, coronary heart disease, cardiac arrhythmias, myocardial ischemia, and hypertrophy. Such renal indications include, but are not limited to, renal failure such as chronic renal failure, acute renal failure and endstage renal failure, renal ischemia and chronic kidney disease. Other indications for which (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption would be, or would be expected to be, beneficial include but are not limited to sleep apnea and ischemic attacks.

Compounds detailed herein may also ameliorate symptoms of a disease or condition that have a cardiac or renal component in which (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption would be, or would be expected to be, beneficial. For example, the compounds may reduce elevated blood pressure, improve shortness of breath, reduce tachycardia, reduce edema, reduce elevated blood urea nitrogen to creatinine (BUN/Cr) ratio, improve creatinine levels, improve the ability to lie flat, reduce the incidence or severity of high blood pressure, reduce the risk and/or number of acute cardiac events (e.g., acute decompensation or myocardial infarction) an individual experiences over a period of time (e.g., one year, 2 years, 5 years, etc.), reduce the incidence of acute heart failure an individual experiences over a period of time (e.g., one year, 2 years, 5 years, etc.), reduce the severity and/or incidence of pulmonary congestion and/or reduce the risk of stroke, reduce shortness of breath and/or tachycardia in individuals after myocardial infarction, improve left ventricular ejection fraction (LVEF) post infarct and/or lower weight and blood pressure in obese individuals (e.g., men and women) with pre-hypertension. In some embodiments, the compounds are adrenergic receptor α_2B antagonists. In some embodiments, the compounds are selective adrenergic receptor α_2B antagonists.

Compounds detailed herein (such as the adrenergic receptor α_2B antagonists detailed herein) may find use in the treatment of hypertensive emergencies. Provided is a method of treating hypertensive emergencies, comprising administering intravenously an effective amount of an adrenergic receptor α_2B antagonist to an individual in need thereof. In some embodiments, the method comprises administering intravenously an effective amount of an adrenergic receptor α_2B antagonist to an individual in need thereof in a highly monitored intensive care setting, wherein the administration results in aggressive and controlled blood pressure lowering in the individual. In some embodiments, intravenous administration of an adrenergic receptor α_2B antagonist in an individual results in gradually lowering of blood pressure in the individual and minimizing damage of end organs such as the brain, kidney, heart, and eye. Particularly useful in the treatment of hypertensive emergencies or crisis are parenteral formulations of an adrenergic receptor α_2B antagonist detailed herein. In one variation, the compound is an adrenergic receptor α_2B antagonist. In some variations, the compound is a selective adrenergic receptor α_2B antagonist. In one variation, the adrenergic receptor α_2B antagonist also exhibits adrenergic receptor α_2A antagonist and/or inverse agonist activity.

In one variation, a method of decreasing the severity and/or incidence of shortness of breath, tachycardia, edema, and/or the inability to lie flat is provided, comprising administering an effective amount of a compound detailed herein to an individual who has or is suspected of having heart failure (e.g., compensated heart failure and decompensated heart failure). In another variation, a method of decreasing the severity and/or incidence of elevated BUN/Cr, and/or edema is provided comprising administering an effective amount of a compound detailed herein to an individual who has or is suspected of having renal failure (e.g., acute or chronic renal failure). In another variation, a method of reducing blood pressure in an individual is provided comprising administering an effective amount of a compound detailed herein to an individual who has or is suspected of having hypertension (e.g., treatment-resistant hypertension). In another variation, a method of decreasing the severity and/or incidence of shortness of breath, tachycardia, and/or improving LVEF post infarct in an individual is provided comprising administering an effective amount of a compound detailed herein to an individual who has experienced myocardial infarction (e.g., an individual who has recently experienced myocardial infarction such as within 30 minutes, 1, 3, 6, 12, or 24 hours of treatment). In some of the variations, the adrenergic receptor α_2B antagonist is a selective adrenergic receptor α_2B antagonist. In some of the variations, the adrenergic receptor α_2B antagonist also exhibits antagonist activity for the adrenergic receptor α_2A. In some embodiments, the compounds are adrenergic receptor α_2B antagonists. In some embodiments, the compounds are selective adrenergic receptor α_2B antagonists.

In one variation, provided is method for lowering the blood pressure in an individual in need thereof comprising administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof. Administration of an adrenergic receptor α_2B antagonist detailed herein lowers the blood pressure in the individual from a level considered above the desired level for such individual. The blood pressure lowering therapy such as administration of compounds detailed herein is intended to help hypertensive individuals reach their blood pressure goals defined by their individual cardiovascular risk factors. For example, for otherwise healthy individuals without diabetes or known cardiovascular disease, goal blood pressure is less than about 140/90 mmHg; for patients with known cardiovascular disease (e.g., prior myocardial infarction, peripheral vascular disease) goal blood pressure is less than about 130-135/85 mmHg; for patients with diabetes, goal blood pressure is less than about 130/80 mmHg.

In one variation, compounds provided herein may have any one or more of the following beneficial effects on an individual: (1) reduce arterial blood pressure (e.g., in an individual with hypertension, certain forms of heart failure and/or renal failure); (2) reduce pulse pressure (e.g., in an individual with hypertension, certain forms of heart failure and/or renal failure); (3) tachycardia-preserved baroreceptor activity (e.g., in an individual whose systolic blood pressure is expected to or does fall in response to an α_2B antagonist), which may suggest a lack of orthostatic hypotension; and (4) bradycardia-reduced cardiac work load and added reduction on blood pressure reduction by further reducing cardiac output (e.g., in an individual who has been administered a therapy that is an α_2B and α_1B mixed antagonist).

In another variation, compounds provided herein may exert their therapeutic effect with no or reduced side-effects, such as when compared to other therapies used in the treatment of the same or similar indication. In one aspect, compounds provided herein exhibit no or reduced side effects upon administration to an individual, wherein the side effects may be any one or more of: (i) reduced libido, (ii) orthostatic hypotension, (iii) muscle weakness, (iv) fatigue, (v) erectile dysfunction, (vi) constipation, (vii) depression, (viii) dizziness, (ix) dry mouth, (x) impaired thinking, (xi) weight gain, (xii) persistent cough, (xiii) chest pain, (xiv) headache, (xv) fluid retention, (xvi) racing pulse, and (xvii) emesis.

In one aspect, compounds are provided that do not bind appreciably any one or more of the histamine, dopamine and serotonin receptors. In any of the methods detailed herein, in one variation the individual does not have a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or neuronal disorder. As used herein, the term “cognitive disorders” refers to and intends diseases and conditions that are believed to involve or be associated with or do involve or are associated with progressive loss of structure and/or function of neurons, including death of neurons, and where a central feature of the disorder may be the impairment of cognition (e.g., memory, attention, perception and/or thinking). These disorders include pathogen-induced cognitive dysfunction, e.g., HIV associated cognitive dysfunction and Lyme disease associated cognitive dysfunction. Examples of cognitive disorders include Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism, mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI) and age-associated memory impairment (AAMI). As used herein, the term “psychotic disorders” refers to and intends mental diseases or conditions that are believed to cause or do cause abnormal thinking and perceptions. Psychotic disorders are characterized by a loss of reality which may be accompanied by delusions, hallucinations (perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space), personality changes and/or disorganized thinking. Other common symptoms include unusual or bizarre behavior, as well as difficulty with social interaction and impairment in carrying out the activities of daily living. Exemplary psychotic disorders are schizophrenia, bipolar disorders, psychosis, anxiety and depression. As used herein, the term “neurotransmitter-mediated disorders” refers to and intends diseases or conditions that are believed to involve or be associated with or do involve or are associated with abnormal levels of neurotransmitters such as histamine, serotonin, dopamine, norepinephrine or impaired function of aminergic G protein-coupled receptors. Exemplary neurotransmitter-mediated disorders include spinal cord injury, diabetic neuropathy, allergic diseases and diseases involving geroprotective activity such as age-associated hair loss (alopecia), age-associated weight loss and age-associated vision disturbances (cataracts). Abnormal neurotransmitter levels are associated with a wide variety of diseases and conditions including, but not limited, to Alzheimer's disease, Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitive impairment, schizophrenia, anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis, depression and a variety of allergic diseases. As used herein, the term “neuronal disorders” refers to and intends diseases or conditions that are believed to involve, or be associated with, or do involve or are associated with neuronal cell death and/or impaired neuronal function or decreased neuronal function. Exemplary neuronal indications include neurodegenerative diseases and disorders such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, canine cognitive dysfunction syndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorder involving cerebral circulation, such as ischemic or hemorrhagic stroke or other cerebral hemorrhagic insult, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), injury-related mild cognitive impairment (MCI), post-concussion syndrome, post-traumatic stress disorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronal death mediated ocular disorder, macular degeneration, age-related macular degeneration, autism, including autism spectrum disorder, Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy, fibromyalgia, neuropathy associated with spinal cord injury, schizophrenia, bipolar disorder, psychosis, anxiety or depression.

Individuals who have high blood pressure, or a disease or condition that is, or is expected to be, responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption may benefit from the compounds detailed herein, including the adrenergic receptor α_2B antagonists (e.g., the selective adrenergic receptor α_2B antagonist) detailed herein.

An individual who does not have high blood pressure or a disease or condition that is, or is expected to be, responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption may nevertheless benefit from the compounds detailed herein if the individual has one or more risk factors for high blood pressure, or a disease or condition that is, or is expected to be, responsive to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption. Risk factors for developing high blood pressure may include gender, race, ethnicity, age, family history, weight and/or lifestyle. For example, African-Americans, men (particularly if over age 45), woman over age 55, anyone over age 60, pre-hypertension individuals (individuals with a blood pressure of 120-130/80-89 mmHg), individuals who are overweight or obese, individuals with sleep apnea (such as obstructive sleep apnea), individuals who smoke, individuals who have a high salt diet, individuals who have a low potassium diet, individuals with chronic heavy alcohol use, individuals with a sedentary lifestyle, individuals with moderate to high stress, individuals with compromised renal function or renal failure and individuals with close relatives who have high blood pressure are each at an increased risk of developing high blood pressure themselves, or diseases or conditions associated with high blood pressure. Individuals with more than one such risk factor are particularly susceptible to developing high blood pressure. Risk factors for developing kidney disease may include diabetes, high blood pressure (hypertension), cardiovascular diseases, smoking, obesity, high cholesterol, a family history of kidney disease, and/or age 65 or older. Members of certain ethnic groups are also at higher risk for kidney disease including people of Aboriginal, Asian, south Asian, Pacific Island, African/Caribbean, American Indian and Hispanic origin.

Cell Viability and Mitochondrial Health

Methods of promoting cellular viability by promoting mitochondrial health are provided, the methods comprising contacting the cell with a compound detailed herein. The methods are applicable to various cells, such as neuronal and non-neuronal cells. In one variation, the cell is a non-neuronal cell, such as a renal or cardiac cell (e.g., myocardial muscle cell). In one aspect, methods of promoting cellular viability are provided wherein the cell is one whose viability would be, or would be expected to be, promoted by nutrient influx and/or oxygenation. Methods of promoting cellular viability in a cell experiencing, or exhibiting symptoms of, mitochondrial stress are also provided.

Methods of treating a disease or condition that is, or is expected to be, responsive to promoting mitochondrial health and cell viability are also described, the methods comprising administering to an individual in need thereof an effective amount of a compound provided herein. In one variation, the disease or condition is one which is associated with dysfunction of mitochondria in a non-neuronal cell. In a particular variation, the disease or condition is one which is associated with dysfunction of mitochondria in a renal or cardiac cell (e.g., myocardial muscle cell). In another variation, the disease or condition is one which would benefit from cellular (e.g., renal or cardiac) nutrient influx and/or oxygenation.

Thus, individuals who have a disease or condition that is associated with, or believed to be associated with, mitochondrial dysfunction may benefit from the compounds detailed herein, or pharmaceutically acceptable salts thereof. An individual who has a disease or condition that is associated with mitochondrial dysfunction should experience one or more beneficial or desirable results upon administration of an effective amount of a compound provided herein, or pharmaceutically acceptable salt thereof. In one aspect, the beneficial or desirable result is an increase in nutrient influx and/or oxygenation of a cell. In another aspect, the beneficial or desirable result is a reduction in the number and/or severity of symptoms associated with a disease or condition that is associated with mitochondrial dysfunction.

In one variation, a method of treating a renal or cardiac condition is provided, comprising administering to an individual in need thereof a compound as detailed herein. Such conditions include, but are not limited to, renal failure, such as acute renal failure and chronic renal failure, coronary (e.g., myocardial) ischemia, heart failure, such as acute and chronic congestive heart failure (including the muscle fatigue associated with these conditions), and coronary artery disease. Methods of treating other diseases and conditions are also described, such as methods of treating sleep apnea, acute respiratory distress syndrome (adult and infant) and peripheral vascular disease. The compounds as provided herein may also be used in a method of delaying the onset and/or development of a disease or condition associated with mitochondrial dysfunction, comprising administering a compound as provided herein, or a pharmaceutical salt thereof, to an individual who is at risk of developing a disease or condition associated with mitochondrial dysfunction.

Compounds that do not bind appreciably to neurotransmitter receptors but nevertheless enhance mitochondrial function, e.g., when administered to cells in the setting of mitochondrial stress (e.g., excess intracellular calcium), may be used in the methods herein to promote cell survival. In one aspect, the compounds exhibit the ability to enhance mitochondrial function by protecting against cell death mediated by mitochondrial dysfunction in an assay detailed herein. Thus, it is understood and clearly conveyed that enhancing mitochondrial function includes protecting a cell against cell death mediated by mitochondrial dysfunction. The compounds may also be assessed in assays known in the art.

It is understood and clearly conveyed that the binding and activity profiles detailed herein (e.g., in the disclosure above) in one variation apply to the formulae provided herein (e.g., the formulae for use in the methods). In one aspect, selective adrenergic receptor α_2B antagonists are of formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), -(D4), and variations thereof.

Compounds of the Invention

Compounds according to the invention are detailed herein, including in the Brief Summary of the Invention and elsewhere. The invention includes the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis/trans or E/Z isomers), salts and solvates of the compounds described herein, as well as methods of making such compounds.

In one aspect, compounds of formulae (A1)-(A2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹ and R^2a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^4a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each R^2a and R^2b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2a and R^2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2a and R^3a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2a and R^4a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^3a and R^3b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3a and R^3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3a and R^2a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3a and R^4a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^4a and R^4b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4a and R^4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4a and R¹ are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4a and R^2a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4a and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o and p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

• • or is taken together with a geminal R^8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, or is taken together with a geminal R^8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,
  • or is taken together with a vicinal R^8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,
  • or is taken together with a vicinal R^8(a-h) to form a bond provided when an R^8(a-h) is taken together with a vicinal R^8(a-h) to form a bond, the geminal R^8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR⁹═CR^10aR^10b, wherein R⁹ is H or a substituted or unsubstituted C₁-C₈ alkyl and R^10a and R^10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety.

In some variations, compounds of the formula (A1), and salts and solvates thereof, are embraced, provided that:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, acyloxy, cyano, alkynyl, acylamino, a group of the formula —CR⁹═CR^10aR^10b, or amino substituted with one or two substituted or unsubstituted C₁-C₈ alkyl; and

(2) when each m, n, o and p is 0 and R⁵ is methyl, then Q is substituted or unsubstituted aryl other than unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, alkynyl, aminocarbonylalkoxy, a group of the formula —CR⁹═CR^10aR^10b, or amino substituted with one or two substituted or unsubstituted C₁-C₈ alkyl;

(3) wherein at least one of m, n, o and p is 1 and R⁵ is H, then Q substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR⁹═CR^10aR^10b; and

(4) wherein at least one of m, n, o and p is 1 and R⁵ is methyl, then Q substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl other than a substituted piperazinyl, aminoacyl, acyloxy, carboxyl, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR⁹═CR^10aR^10b, or amino substituted with one or two substituted or unsubstituted C₁-C₈ alkyl.

In one variation, compounds of the formula (A1), and salts and solvates thereof, are embraced, provided that when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, at least one of m, n, o and p is 1 and each R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R^8(a-h) to form a substituted or unsubstituted methylene moiety or is taken together with a geminal R^8(a-h) and the carbon to which they are attached to form a carbonyl moiety, then:

(i) when Q is a carbonylalkoxy of the formula —COOCH₃ and R⁵ is an unsubstituted C₁-C₈ alkyl where the unsubstituted C₁-C₈ alkyl is methyl, then one or more of provisions (a)-(d) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^2a and R^2b are both H; (c) R¹ is H or an unsubstituted C₁-C₈ alkyl; and (d) R⁵ is H;
(ii) when either (1) Q is carbonylalkoxy of the formula —COOCH₃ or —COOCH₂CH₃ or (2) Q is an alkoxy of formula —OCH₃ or —OCH₂CH₃ and is bound to a carbonyl group to form a moiety of the formula —COOCH₃ or —COOCH₂CH₃, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶, provided that if X² is CR⁶ where R⁶ is methyl, then R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) at least one of n, m, o and p is 1;
(iii) when either (1) Q is an acylamino of the formula —CONH₂ or (2) Q is an unsubstituted amino bound to a carbonyl group to form a moiety of the formula —CONH₂, then one or more of provisions (a)-(e) apply: (a) at least one of X¹, X² and X³ is N or CR⁶, provided that if X² is CR⁶ where R⁶ is methyl, then R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R⁵ is an unsubstituted C₂-C₈ alkyl; (c) R⁵ and R¹ are independently an unsubstituted C₁-C₈ alkyl; (d) at least one of n, m, o and p is 1; and (e) when R⁵ is an unsubstituted C₁-C₈ alkyl, then R^2a and R^2b are both H;
(iv) when Q is cyano, then one or more of provisions (a)-(d) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^2a and R^2b are both H; (c) R¹ is an unsubstituted C₁-C₈ alkyl; and (d) at least one of n, m, o and p is 1;
(v) when Q is an acyloxy of the formula —COOH, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) at least one of n, m, o and p is 1;
(vi) when Q is an acyloxy of the formula —COO-substituted alkyl, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) R¹ is other than H.

In some variations, compounds of the formula (A2), and salts and solvates thereof, are embraced, provided that:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted or unsubstituted aryl other than unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, cyano, alkynyl, aminocarbonylalkoxy, acylamino, a group of the formula —CR⁹═CR^10aR^10b, or amino substituted with one or two substituted or unsubstituted C₁-C₈ alkyl;

(2) when each m, n, o and p is 0 and R⁵ is unsubstituted C₁-C₈ alkyl, then Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR⁹═CR^10aR^10b; and

(3) when at least one of m, n, o and p is 1 and R⁵ is H, then Q is substituted or unsubstituted aryl other than unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted amino, aminoacyl, acyloxy, cyano, alkynyl, aminocarbonylalkoxy, or is a group of the formula —CR⁹═CR^10aR^10b.

In one variation, compounds of the formula (A2), and salts and solvates thereof, are embraced, provided that:

(i) when m, n, o and p are each 0 and Q is a substituted aryl wherein the substituted aryl is a carboline moiety, then one or more of provisions (a)-(c) apply: (a) X¹, X² and X³ are independently N or CH; (b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) R¹ is an unsubstituted C₁-C₈ alkyl;
(ii) when none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, at least one of m, n, o and p is 1 and each R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R^8(a-h) to form a substituted or unsubstituted methylene moiety or is taken together with a geminal R^8(a-h) and the carbon to which they are attached to form a carbonyl moiety, then:

(A) when Q is a carboxyl moiety, then one or more of provisions (a)-(e) apply: (a) at least one of X¹, X² and X³ is independently N or CR⁶; (b) two or more of m, n, o and p are 1; (c) at least one of R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h is other than H; (d) when R⁵ is an unsubstituted C₁-C₈ alkyl then at least one of m, n, o and p is 1; and (e) when R⁵ is H then R^2a and R^2b are each H;

(B) when one of R^2a and R^2b is methyl or when R^2a and R^2b are taken together to form a carbonyl, then one or more of provisions (a)-(c) apply: (a) R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R¹ is an unsubstituted C₁-C₈ alkyl; and (c) Q is a substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, aminoacyl, cyano, alkynyl, aminocarbonylalkoxy; and

(C) when R¹ and R^2a are taken together to form a butylene (—CH₂CH₂CH₂CH₂—), then one or more of provisions (a)-(d) apply: (a) R⁵ is an unsubstituted C₁-C₈ alkyl; (b) the 6-membered ring formed when R¹ and R^2a are taken together to form a butylene (—CH₂CH₂CH₂CH₂—) moiety is not further substituted with a cyclic structure and is not substituted with an alkenyl or cyano-containing moiety; (c) X³ is CH and X¹ and X² are independently N or CR⁶; and (d) Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino moiety.

In specific variations, compounds of formula (A1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶, X¹, X², X³, R^8(a-h), m, n, o, p and Q, where present, are defined as for formula (A1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (A1) detailed throughout, where applicable, apply equally to any of formulae (A1a)-(A1c) the same as if each and every variation were specifically and individually listed for formulae (A1a)-(A1c). Pharmaceutically acceptable salts of compounds of formulae (A1a)-(A1c) are also provided.

In specific variations, compounds of formula (A1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X², X³, R^8(a-h) and Q, where present, are defined herein and, where applicable, any variation thereof detailed herein. That is, variations of the formula (A1) detailed throughout, where applicable, apply equally to any of formulae (A1d)-(A1h) the same as if each and every variation were specifically and individually listed for formulae (A1d)-(A1h). Pharmaceutically acceptable salts of compounds of formulae (A1d)-(A1h) are also provided.

In another variation, compounds of formula (A1) have the structure:

or a salt or solvate thereof; wherein R⁵, R^8(a-h), X¹, X², X³ and Q, where present, are defined herein and, where applicable, any variation thereof detailed herein. That is, variations of the formula (A1) detailed throughout, where applicable, apply equally to any of formulae (A1i)-(A1r) the same as if each and every variation were specifically and individually listed for formulae (A1i)-(A1r). In one embodiment, compounds of the formula (A1) are provided wherein the compounds are of the formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) being taken together with R^2a of formula (A1) to provide compounds of the formula (A1i)-(A1r), R¹ is taken together with R^3a to form a propylene moiety or a butylene moiety. In another embodiment, compounds of the formula (A1) are provided wherein the compounds are of the formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) being taken together with R^2a of formula (A1) to provide compounds of the formula (A1i)-(A1r), R¹ is taken together with R^4a to form an ethylene moiety or a propylene moiety. In a further embodiment, compounds of the formula (A1) are provided wherein the compounds are of the formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) being taken together with R^2a of formula (A1) to provide compounds of the formula (A1i)-(A1r), R^2a and R^3a are taken together to form an ethylene moiety or a propylene moiety. In still a further embodiment, compounds of the formula (A1) are provided wherein the compounds are of the formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) being taken together with R^2a of formula (A1) to provide compounds of the formula (A1i)-(A1r), R^2a and R^4a are taken together to form a methylene moiety or an ethylene moiety. In yet another embodiment, compounds of the formula (A1) are provided wherein the compounds are of the formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) being taken together with R^2a of formula (A1) to provide compounds of the formula (B1)-(B10), R^3a and R^4a are taken together to form a propylene moiety or a butylene moiety. Variations detailed throughout, where applicable, apply to such formulae the same as if each and every variation were specifically and individually listed. Pharmaceutically acceptable salts of such formulae are also provided. Pharmaceutically acceptable salts of compounds of formulae (A1i)-(A1r) are also provided.

All variations referring to the formulae herein, such as formulae (A1a)-(A1r), where applicable, may apply to formula (A2), the same as if each and every variation were specifically and individually listed.

In some embodiments, compounds of the formula (A1a) have the structures (F1)-(F5):

wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^8c, where present, is H, OH or substituted or unsubstituted C₁-C₈ alkyl;

R^8d, where present, is H or substituted or unsubstituted C₁-C₈ alkyl, and the bond indicates the presence of either an E or Z double bond configuration;

Y, where present, is O or NR¹¹;

each R¹¹, R^12a and R^12b is independently H or substituted or unsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

provided that when the compound is of the formula (F5), D is other than unsubstituted phenyl.

In some embodiments, the compound is of the formula (F1). In some embodiments, wherein the compound is of the formula (F2). In some embodiments, the compound is of the formula (F3). In some embodiments, the compound is of the formula (F4). In some embodiments, the compound is of the formula (F5).

In another aspect, compounds of formulae (A3)-(A4) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^2a, R^2b R^3a, R^3b, R^4a, R^4b, R^10a and R^10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

• • or is taken together with a geminal R^8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, or is taken together with a geminal R^8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,
  • or is taken together with a vicinal R^8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,
  • or is taken together with a vicinal R^8(a-h) to form a bond provided when an R^8(a-h) is taken together with a vicinal R^8(a-h) to form a bond, the geminal R^8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR⁹═CR^10aR^10b, wherein R⁹ is H or a substituted or unsubstituted C₁-C₈ alkyl and R^10a and R^10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety.

In a particular variation, compounds of formula (A3) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶ and R^8(a-h), where present, and Q are defined as for formula (A3) and, where applicable, any variation thereof detailed herein. That is, variations of formula (A3) detailed throughout, where applicable, apply to formulae (A3a)-(A3e) the same as if each and every variation were specifically and individually listed for formulae (A3a)-(A3e). Pharmaceutically acceptable salts of compounds of formulae (A3a)-(A3e) are also provided.

In particular variation, compounds of formula (A3) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X² and X³ are defined as for formula (A3) and, where applicable, any variation thereof detailed herein, n is 0-5, o is 0-4, p is 0-3, Z is NH, N—CH₃, O or S, and W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino. In one particular aspect of this variation, W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one particular aspect of this variation, Z is S. In another particular aspect of this variation, one of X¹, X² or X³ is N. Variations of formula (A3) detailed throughout, where applicable, apply equally to any of formulae (A3f)-(A3h), the same as if each and every variation were specifically and individually listed for formula (A3f)-(A3h). Pharmaceutically acceptable salts of compounds of formulae (A3f)-(A3h) are also provided.

All variations referring to the formulae herein, such as formulae (A3a)-(A3h), where applicable, may apply to formula (A4), the same as if each and every variation were specifically and individually listed.

In another aspect, compounds of formulae (B1)-(B2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹ and R^2a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^4a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each R^2a and R^2b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2a and R^2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^2a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2a and R^3a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2a and R^4a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^3a and R^3b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3a and R^3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3a and R^2a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3a and R^4a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^4a and R^4b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^4a and R^4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^4a and R¹ are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4a and R^2a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4a and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^5a and R^5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^5a and R^5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R^5a and R^7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R^5a and R^7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R^5a and R^7e are taken together to form a bond, or

when m-o are each 1, then R^5a and R^7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X¹, X² and X³ is independently N, CH or CR⁶;

Y¹ is CR^7aR^7b, NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^7cR^7d;

Y², where present, is CR^7cR^7d, NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^7aR^7b and Y³, where present, is CR^7eR^7f;

Y³, where present, is CR^7eR^7f, NR⁸, O, S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^7cR^7d and Y⁴, where present, is CR^7gR^7h;

Y⁴, where present, is CR^7gR^7h, NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^7eR^7f;

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^7a and R^7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7a and R^7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7a and R^7c, where present, are taken together to form a bond;

each R^7c and R^7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7c and R^7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7c and R^7a, where present, are taken together to form a bond, or R^7c and R^7e are taken together to form a bond;

each R^7e and R^7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7e and R^7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7e and R^7c are taken together to form a bond, or R^7e and R^7g, where present, are taken together to form a bond;

each R^7g and R^7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7g and R^7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or

R^7g and R^7e are taken together to form a bond, or R^7g and R^5a are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In one variation, compounds of the formula (B1) where m-o are each 0, and salts and solvates thereof, are embraced, provided that when Y¹ is CR^7aR^7b where R^7a and R^7b are both H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then (i) at least one of R^5a and R^5b is other than H, and (ii) when at least one of R^5a and R^5b is other than H, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^5a and R^5b are both other than H; and (c) R^5a is H and R^5b is an unsubstituted aryl other than phenyl.

In another variation, compounds of the formula (B1) where m-o are each 0, and salts and solvates thereof, are embraced, provided that when Y¹ is CR^7aR^7b where R^7a and R^7b are both H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then (i) when each R^5a and R^5b is H, at least one of X¹, X² and X³ is N or CR⁶ where R⁶ is other than unsubstituted and substituted phenyl; and (ii) when at least one of R^5a and R^5b is other than H, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^5a and R^5b are both other than H; and (c) R^5a is H and R^5b is an unsubstituted aryl other than phenyl.

In one variation, compounds of the formula (B2) where m-o are each 0, and salts and solvates thereof, are embraced, provided that when Y¹ is CR^7aR^7b where R^7a and R^7b are both H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then at least one of R^5a and R^5b is other than H.

In one variation, compounds of the formula (B1) where m is 1 and n-o are each 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y² is CR^7cR^7d where R^7c and R^7d are each H and Y¹ is O or CR^7aR^7b where R^7a and R^7b are each H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then (i) at least one of R^5a and R^5b is other than H, and (ii) when at least one of R^5a and R^5b is other than H, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^5a and R^5b are each other than H; and (c) at least one of R^5a and R^5b is a substituted or unsubstituted heteroaryl, a substituted aryl or an unsubstituted aryl other than phenyl;

(2) when Y² is CR^7cR^7d where R^7c and R^7d are each H and Y¹ is S and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then (i) at least one of R^5a and R^5b is other than H, and (ii) when at least one of R^5a and R^5b is other than H, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^5a and R^5b are each other than H; and (c) at least one of R^5a and R^5b is a substituted or unsubstituted heteroaryl or aryl moiety;

(3) when Y¹ is NH, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, and R^7c, if present, is not taken together with R^5a to form a bond, then one or more of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) Y² is other than C(O); and (c) at least one of R^5a and R^5b is other than H; and

(4) when Y¹ is NR⁸ where R⁸ is methyl, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, and R^7c, if present, is not taken together with R^5a to form a bond, then one or both of provisions (a) and (b) apply: (a) at least one of X¹, X² and X³ is N or CR⁶ and (b) at least one of R^5a and R^5b is other than H and methyl.

In another variation, compounds of the formula (B1) where m is 1 and n-o are each 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^7aR^7b where R^7a and R^7b are each H, Y² is CR^7cR^7d where R^7c and R^7d are each H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or more of provisions (i)-(iii) apply: (i) at least one of R^5a and R^5b is other than H and at least one of X¹, X² and X³ is N or CR⁶; (ii) when each of R^5a and R^5b is H, at least one of X¹, X² and X³ is N or CR⁶ where R⁶ is chloro or substituted or unsubstituted alkyl (e.g., methyl); and (iii) when each of X¹, X² and X³ is CH, at least one of R^5a and R^5b is other than H, phenyl and CH₂CH₂NMe₂;

(2) when Y¹ is O or S and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then (i) when Y² is CR^7cR^7d where R^7c and R^7d are each H, at least one of R^5a and R^5b is other than H; or (ii) when Y² is CR^7cR^7d where one of R^7c and R^7d is H and the other is phenyl, at least one of R^5a and R^5b is other than H or at least one of X¹, X² and X³ is N or CR⁶;

(3) when Y¹ is NR⁸ where R⁸ is H, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, and R^7c is not taken together with R^5a to form a bond, then one or both of provisions (i) and (ii) apply: (i) at least one of X¹, X² and X³ is N or CR⁶; and (ii) Y² is CR^7cR^7d where R^7c and R^7d are not taken together with the carbon to which they are attached to form a carbonyl moiety;

(4) when Y¹ is NR⁸ where R⁸ is methyl, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, and R^7c is not taken together with R^5a to form a bond, then at least one of X¹, X² and X³ is N or CR⁶; and

(5) when Y² is CR^7cR^7d where R^7c and R^7d are taken together with the carbon to which they are attached to form a carbonyl moiety, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, and each of X¹, X² and X³ is CH, then Y¹ is not NR⁸ where R⁸ is an alkyl substituted with a substituted amino group (e.g., (CH₂)₃NMe₂).

In one variation, compounds of the formula (B2) where m is 1 and n-o are each 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^7aR^7b and Y² is CR^7cR^7d where each of R^7a, R^7b, R^7c and R^7d is H, R^2a and R^2b are taken together with the carbon to which they are attached to form a cycloalkyl moiety, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or more of provisions (a)-(d) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^5a is H and R^5b is other than H; (c) at least one of R^5a and R^5b is a unsubstituted or unsubstituted heteroaryl or aryl moiety; and (d) R¹ is a substituted or unsubstituted C₁-C₈ alkyl;

(2) when Y¹ is NH, Y² is CR^7cR^7d where R^7c and R^7d are each H, none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, and R^7c, if present, is not taken together with R^5a to form a bond, then (i) at least one of R^5a and R^5b is other than H, and (ii) when at least one of R^5a and R^5b is other than H, then one or both of provisions (a) and (b) apply: (a) at least one of R^5a and R^5b is other than an unsubstituted C₁-C₈alkyl; (b) R¹ is a substituted or unsubstituted C₁-C₈ alkyl and at least one of X¹, X² and X³ is N or CR⁶; and

(3) when Y¹ is O, Y² is CR^7cR^7d where R^7c and R^7d are each H, none of R, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, and R^7c, if present, is not taken together with R^5a to form a bond, then one or more of provisions (a)-(d) apply: (a) when R^5a is H then R^5b is other than an unsubstituted C₁-C₈alkyl; (b) only one or more than two of X¹, X² and X³ is CR⁶; (c) R¹ is other than H; and (d) at least one of R^2a and R^2b is H.

In another variation, compounds of the formula (B2) where m is 1 and n-o are each 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^7aR^7b and Y² is CR^7cR^7d where each of R^7a, R^7b, R^7c and R^7d is H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring except that R^2a and R^2b may be taken together with the carbon to which they are attached to form a cycloalkyl moiety, then (i) at least one of R^5a and R^5b is other than H, and (ii) when one of R^5a and R^5b is an unsubstituted C₁-C₈alkyl, at least one of X¹, X² and X³ is N or CR⁶;

(2) when Y¹ is CR^7aR^7b where both of R^7a and R^7b are unsubstituted C₁-C₈alkyl, Y² is CR^7cR^7d where each R^7c and R^7d is H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then (i) at least one of R^5a and R^5b is other than H, or (ii) R¹ is a other than H; and

(3) when Y¹ is O, Y² is CR^7cR^7d where R^7c and R^7d are each H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or more of provisions (a)-(d) apply: (a) when R^5a is H then R^5b is other than an unsubstituted C₁-C₈alkyl; (b) only one or more than two of X¹, X² and X³ is CR⁶; (c) R¹ is other than H; and (d) at least one of R^2a and R^2b is H.

In one variation, compounds of the formula (B1) where m-n are each 1 and o is 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^7aR^7b, Y² is CR^7cR^7d and Y³ is CR^7eR^7f where each of R^7a, R^7b, R^7c, R^7d, R^7e and R^7f are H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or both of provisions (a) and (b) apply: (a) at least one of R^5a and R^5b is other than H; and (b) R¹ is an unsubstituted C₁-C₈ alkyl;

(2) when Y¹ is S or CR^7aR^7b, Y² is S, S(O) or CR^7cR^7d and Y³ is CR^7eR^7f where each of R^7a, R^7b, R^7c, R^7d, R^7e and R^7f, if present, is H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring and where either Y¹ is S and Y² is CR^7cR^7d or Y² is S or S(O) and Y¹ is CR^7aR^7b, then (i) at least one of R^5a and R^5b is other than H, and (ii) when at least one of R^5a and R^5b is other than H, then one or both of provisions (a) and (b) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; and (b) R¹ is methyl and at least one of R^5a and R^5b is a substituted or unsubstituted heteroaryl or aryl moiety;

(3) when Y¹ is O or CR^7aR^7b, Y² is O or CR^7cR^7d and Y³ is CR^7eR^7f where each of R^7a, R^7b, R^7c, R^7d, R^7e and R^7f, if present, is H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring and where either Y¹ is O and Y² is CR^7cR^7d or Y² is O and Y¹ is CR^7aR^7b, then (i) at least one of R^5a and R^5b is other than H, and (ii) when at least one of R^5a and R^5b is other than H, then one or both of provisions (a) and (b) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; and (b) R¹ is other than H; and

(4) when Y¹ is NH and Y³ is CR^7eR^7f, where R^7e and R^7f are both H, and where none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring then (i) at least one of R^5a and R^5b is other than H and (ii) when Y² is CR^7cR^7d, R^7c and R^7d are not taken together to form a carbonyl moiety.

In another variation, compounds of the formula (B1) where m-n are each 1 and o is 0, and salts and solvates thereof, are embraced, provided that when R^5a and R^5b is H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or more of provisions (1) to (5) apply:

(1) when Y³ is CR^7eR^7f where one of R^7e and R^7f is an unsubstituted C₁-C₈alkyl, then one or more of provisions (i) to (iv) apply: (i) at least one of X¹, X² and X³ is N or CR⁶; (ii) Y² is other than CR^7cR^7d where each of R^7c and R^7d is H; (iii) Y¹ is other than S; and (iv) R¹ is other than H;

(2) when Y² is CR^7cR^7d and Y³ is CR^7eR^7f where each of R^7c, R^7d, R^7e and R^7f is H, then (i) Y¹ is other than CR^7aR^7b where each of R^7a and R^7b is H and NR⁸ where R⁸ is H; and (ii) when Y¹ is O, S or S(O), X² is N or CR⁶;

(3) when Y³ is CR^7eR^7f where each of R^7e and R^7f is H and Y² is CR^7cR^7d where at least one of R^7c and R^7d is other than H, then one or both provisions (i) and (ii) apply: (i) at least one of X¹, X² and X³ is N or CR⁶; and (ii) Y¹ is other than S and NH;

(4) when Y² is S and Y³ is CR^7eR^7f where each R^7e and R^7f is H, then one or more of provisions (i) to (iii) apply: (i) at least one of X¹, X² and X³ is N or CR⁶; (ii) Y¹ is CR^7aR^7b where at least one of R^7a and R^7b is other than H; and (iii) R¹ is other than H; and

(5) when Y² is O and Y³ is CR^7eR^7f where each R^7e and R^7f is H, then (i) Y¹ is CR^7aR^7b where at least one of R^7a and R^7b is other than H; and (ii) when Y¹ is CR^7aR^7b where one of R^7a and R^7b is methyl or phenyl, then one or both of provisions (a) and (b) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; and (b) R¹ is other than H.

In one variation, compounds of the formula (B2) where m-n are each 1 and o is 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^7aR^7b, Y² is CR^7cR^7d and Y³ is CR^7eR^7f where each of R^7a, R^7b, R^7e and R^7f are H and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then (i) when R^7c and R^7d are both H, at least one of R^5a and R^5b is other than H, and (ii) when R^7c and R^7d are both methyl, then one or both of provisions (a) and (b) apply: (a) R^2a and R^2b are both H and (b) at least one of X¹, X² and X³ is N or CR⁶;

(2) when Y¹ is S or O, Y² is CR^7cR^7d and Y³ is CR^7eR^7f where each of R^7c, R^7d, R^7e and R^7f is H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or both of provisions (a) and (b) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; and (b) at least one of R^5a and R^5b is other than H.

In one variation, compounds of the formula (B1) where m-o are each 1, and salts and solvates thereof, are embraced, provided that:

when Y¹ is CR^7aR^7b, Y² is CR^7cR^7d, Y³ is CR^7eR^7f and Y⁴ is CR^7gR^7h where each of R^7a, R^7b, R^7c, R^7d, R^7e, R^7f, R^7g and R^7h are H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or more of provisions (a)-(c) apply: (a) at least one of R^5a and R^5b is other than H; (b) at least one of X¹, X² and X³ is N or CR⁶; and (c) R¹ is other than H.

In another variation, compounds of the formula (B1) where m-o are each 1, and salts and solvates thereof, are embraced, provided that when Y¹ is CR^7aR^7b where each R^7a and R^7b is H, Y² is S, Y³ is CR^7eR^7f where each R^7e and R^7f is H, Y⁴ is CR^7gR^7h where each R^7g and R^7h is H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or more of provisions (i)-(iii) apply: (i) at least one of R^5a and R^5b is other than H; (ii) at least one of X¹, X² and X³ is N or CR⁶; and (iii) R¹ is other than H.

In one variation, compounds of the formula (B2) where m-o are each 1, and salts and solvates thereof, are embraced, provided that:

when Y¹ is CR^7aR^7b, Y² is CR^7cR^7d, Y³ is CR^7eR^7f and Y⁴ is CR^7gR^7h where each of R^7a, R^7b, R^7c, R^7d, R^7e, R^7f, R^7g and R^7h are H, and none of R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are taken together to form a ring, then one or more of provisions (a)-(c) apply: (a) at least one of R^5a and R^5b is other than H; (b) at least one of X¹, X² and X³ is N or CR⁶; and (c) R¹ is other than H.

In specific variations, compounds of the formula (B1) have the structure:

or a salt or solvate thereof; wherein R¹, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁶, R^7(a-h), X¹, X², X³, Y¹, Y², Y³ and Y⁴, where present, are defined as for formula (B1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (BI) detailed throughout, where applicable, apply to formulae (B1a)-(B1bm), the same as if each and every variation were specifically and individually listed for formulae (B1a)-(B1bm). Pharmaceutically acceptable salts of compounds of formulae (B1a)-(B1bm) are also provided.

In some variations, compounds of formula (B1) where m is 1 and n-o are each 0 have the structure (B1bl), provided that:

(1) when Y¹ is CR^7aR^7b where each R^7a and R^7b is H, then one or both of provisions (i) and (ii) apply: (i) R⁶ is other than H, fluoro, methoxy, unsubstituted phenyl and substituted phenyl; and (ii) at least one of R^7c and R^7d is other than H; and

(2) when Y¹ is NR⁸, O, S, S(O) or SO₂, then (iii) R^7c and R^7d are not taken together with the carbon to which they are attached to form a carbonyl; and (iv) at least one of R^7c and R^7d is other than H, methyl and unsubstituted phenyl.

In some variations, compounds of formula (B1) where m is 1 and n-o are each 0 have the structure (B1bm), provided that:

(1) when Y¹ is CR^7aR^7b where each R^7a and R^7b is H, then R⁶ is other than H, fluoro, methoxy, unsubstituted phenyl and substituted phenyl; and

(2) when Y¹ is NR⁸, O, S, S(O) or SO₂, then at least one of R^5a and R^5b is other than H.

In some variations of formulae (B1), (B1a), (B1d), (B1g), (B1j), (B1m), (B1s), (B1v) and (B1y)-(B1ap), at least one of X¹, X² and X³ is N. In another variation, one of X¹, X² and X³ is N. In one variation, X¹ is N and each X² and X³ is independently CH or CR⁶. In another variation, X² is N and each X¹ and X³ is independently CH or CR⁶. In yet another variation, X³ is N and each X¹ and X² is independently CH or CR⁶. In another variation, two of X¹, X² and X³ is N. In one variation, each X¹ and X³ is N and X is CH or CR⁶.

All variations referring to the formulae herein, such as formulae (B1a)-(B1bm), where applicable, may apply to formula (B2), the same as if each and every variation were specifically and individually listed.

In another aspect, compounds of formulae (B3)-(B4) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^2a, R^2b R^3a, R^3b, R^4a, R^4b, R^10a and R^10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

each R^5a and R^5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^5a and R^5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R^5a and R^7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R^5a and R^7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R^5a and R^7e are taken together to form a bond, or

when m-o are each 1, then R^5a and R^7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X¹, X² and X³ is independently N, CH or CR⁶;

Y¹ is CR^7aR^7b, NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^7cR^7d;

Y², where present, is CR^7cR^7d, NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR^8b, O, S, S(O) or SO₂, then Y¹ is CR^7aR^7b and Y³, where present, is CR^7eR^7f;

Y³, where present, is CR^7eR^7f, NR⁸, O, S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^7cR^7d and Y⁴, where present, is CR^7gR^7h;

Y⁴, where present, is CR^7gR^7h, NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^7eR^7f;

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^7a and R^7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7a and R^7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7a and R^7c, where present, are taken together to form a bond;

each R^7c and R^7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7c and R^7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or

R^7c and R^7a are taken together to form a bond, or R^7c and R^7e, where present, are taken together to form a bond;

each R^7e and R^7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7e and R^7f, where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7e and R^7c are taken together to form a bond, or R^7e and R^7g, where present, are taken together to form a bond;

each R^7g and R^7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7g and R^7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7g and R^7e are taken together to form a bond, or R^7g and R^5a are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In a particular variation, compounds of formula (B3) have the structure:

or a salt or solvate thereof; wherein R¹, R^5a, R^5b, R⁶, Y¹, Y², Y³ and Y⁴, where present, are defined as for formulae (B3) and, where applicable, any variation thereof detailed herein. That is, variations of formulae (B3) detailed throughout, where applicable, apply to formulae (B3a)-(B3d) the same as if each and every variation were specifically and individually listed for formulae (B3a)-(B3d). Pharmaceutically acceptable salts of compounds of formulae (B3a)-(B3d) are also provided.

All variations referring to the formulae herein, such as formulae (B3a)-(B3d), where applicable, may apply to formula (B4), the same as if each and every variation were specifically and individually listed.

In some embodiments, compounds of the formula (B5) are provided:

or a salt or solvate thereof; wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

each R^5a and R^5b is independently H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aralkyl, or R^5a is taken together with a vicinal R^7(a-f) to form a bond;

Z¹ is O or CR^7aR^7b;

Z² is a bond or CR^7cR^7d;

Z³ is a bond or CR^7eR^7f;

R⁶ is H, chloro, or substituted or unsubstituted C₁-C₈ alkyl; and

each R^7a, R^7b, R^7c, R^7d, R^7e and R^7f, when present, is independently H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aralkyl, or is taken together with a vicinal R^7(a-f) or R^5a to form a bond.

In one variation, compounds of the formula (B5), and salts and solvates thereof, are embraced, provided that:

(1) when Z¹ is CR^7aR^7b and at least one of Z² and Z³ is a bond, then one or both of provisions (i) and (ii) apply: (i) R⁶ is chloro or substituted or unsubstituted C₁-C₈ alkyl; and (ii) at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e and R^7f, when present, is other than H and unsubstituted phenyl;

(2) when Z¹ is O and at least one of Z² and Z³ is a bond, then (iii) at least one of R^5a, R^5b R^7c, R^7d, R^7e and R^7f, when present, is other than H; and (iv) when one of R^7c, R^7d, R^7e and R^7f, when present, is unsubstituted phenyl, R⁶ is chloro or substituted or unsubstituted C₁-C₈ alkyl; and

(3) when Z² is CR^7cR^7d and Z³ is CR^7eR^7f, then one or both of provisions (v) and (vi) apply: (v) R⁶ is chloro or substituted or unsubstituted C₁-C₈ alkyl; and (vi) at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e and R^7f, when present, is other than H.

In another aspect, compounds of formulae (C1)-(C2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^2a, where present, are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R⁴, where present, are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^4a, where present, are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each R², R^2a and R^2b, where present, is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2a and R^2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R² and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R² and R^3a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2a and R^3a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^2a and R⁴ are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R² and a vicinal R^8(a-h) are taken together to form a bond;

each R^3a and R^3b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3a and R^3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3a and R² are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3a and R^2a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3a and R⁴ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety or R^3a and R^4a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R⁴ or R^4a, where present, is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4a and R¹ are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R⁴ and R^2a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4a and R^2a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R⁴ and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^4a and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ and a vicinal R^8(a-h) are taken together to form a bond;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

each m, n, o and p is independently 0 or 1;

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

• • or is taken together with a geminal R^8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, or is taken together with a geminal R^8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,
  • or is taken together with a vicinal R^8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,
  • or is taken together with a vicinal R^8(a-h) to form a bond provided when an R^8(a-h) is taken together with a vicinal R^8(a-h) to form a bond, the geminal R^8(a-h) is other than hydroxyl and thiol and thiol,
  • or is taken together with vicinal R², where present, to form a bond,
  • or is taken together with vicinal R⁴, where present, to form a bond; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR⁹═CR^10aR^10b, wherein R⁹ is H or a substituted or unsubstituted C₁-C₈ alkyl and R^10a and R^10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety.

In some variations, the compound is of the formula (C1), wherein R¹, R^2a, R^2b, R^3a, R^3b R⁴, R⁵, m, n, o, p, R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g, R^8h, X¹, X², X³, X⁴ and Q are as defined for formula (C1), provided that one or more of (i)-(iii) applies: (i) when none of R¹, R^2a, R^2b, R^3a R^3b and R⁴ are taken together to form a ring, at least one of m, n, o and p is 1, none of R^8a, R^8b R^8c, R^8d, R^8e, R^8f, R^8g and R^8h is taken together with a vicinal R^8(a-h) and the carbon atoms to which they are attached to form a ring and R⁵ is H, Q is other than carboxyl, carbonylalkoxy and unsubstituted phenyl; (ii) at least two of R¹, R^2a, R^2b, R^3a, R^3b and R⁴ are taken together to form a ring; and (iii) at least one of m, n, o and p is 1 and at least one of R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h is taken together with a vicinal R^8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety.

In some variations, the compound is of the formula (C2), wherein R¹, R², R^3a, R^3b, R^4a R^4b, R⁵, m, n, o, p, R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g, R^8h, X¹, X², X³, X⁴ and Q are as defined for formula (C2), provided that at least one of m, n, o and p is 1 and one or more of (i)-(v) applies: (i) when none of R¹, R², R^3a, R^3b, R^4a and R^4b are taken together to form a ring and each X¹, X², X³, and X⁴ is CH, R⁵ is an unsubstituted C₂-C₈ alkyl and Q is other than cyano, aminocarbonyl, dimethylamino and 4-methyl-1-piperazinyl; (ii) when none of R¹, R², R^3a, R^3b, R^4a and R^4b are taken together to form a ring, each X¹, X³, and X⁴ is CH and X² is CR⁶ where R⁶ is chloro or methoxy, R⁵ is an unsubstituted C₂-C₈ alkyl and Q is other than carbonylalkoxy and cyclobutyl; (iii) when R¹ and R² are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety and both of R^3a and R^3b are H, Q is other than carboxyl or carbonylalkoxy; (iv) when R¹ and R^4a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, X² is CH or CR⁶ where R⁶ is methoxy, benzyloxy or methylthio and both of R^3a and R^3b are H, Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C₃-C₈ cycloalkylidene, a substituted or unsubstituted C₃-C₈ cycloalkenylidene, or a substituted or unsubstituted heterocyclylidene, substituted amino, aminoacyl, acyloxy, cyano, alkynyl or aminocarbonylalkoxy; and (v) when R^3a and R^4a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, both of R^3b and R^4b are H and only one of m, n, o, p is 1, Q is other than carboxyl, 1-naphthyl and 3,4-dimethoxyphenyl.

In specific variations, compounds of formula (C1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶, X¹, X², X³, X⁴, R^8(a-h), m, n, o, p and Q are defined as for formula (C1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (C1) detailed throughout, where applicable, apply equally to any of formulae (C1-a)-(C1-c) the same as if each and every variation were specifically and individually listed for formulae (C1-a)-(C1-c). Pharmaceutically acceptable salts of compounds of formulae (C1-a)-(C1-c) are also provided.

In specific variations, compounds of formula (C1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X², X³, X⁴, R^8(a-h) and Q, where present, are defined herein and, where applicable, any variation thereof detailed herein. That is, variations of the formula (C1) detailed throughout, where applicable, apply equally to any of formulae (C1d)-(C1-h) the same as if each and every variation were specifically and individually listed for formulae (C1d)-(C1-h). Pharmaceutically acceptable salts of compounds of formulae (C1d)-(C1-h) are also provided.

In another variation, compounds of formula (C1) have the structure:

or a salt or solvate thereof; wherein R⁵, R^8(a-h), X¹, X², X³, X⁴ and Q, where present, are defined herein and, where applicable, any variation thereof detailed herein. That is, variations of the formula (C1) detailed throughout, where applicable, apply equally to any of formulae (C1i)-(C1r) the same as if each and every variation were specifically and individually listed for formulae (C1i)-(C1r). In one embodiment, compounds of the formula (C1) are provided wherein the compounds are of the formula (C1i)-(C1r) except that, instead of R¹ of formula (C1) being taken together with R^2a of formula (IA) to provide compounds of the formula (C1i)-(C1r), R¹ is taken together with R^3a to form a propylene moiety or a butylene moiety. In another embodiment, compounds of the formula (C1) are provided wherein the compounds are of the formula (C1i)-(C1r) except that, instead of R¹ of formula (C1) being taken together with R^2a of formula (C1) to provide compounds of the formula (C1i)-(C1r), R¹ is taken together with R⁴ to form an ethylene moiety or a propylene moiety. In a further embodiment, compounds of the formula (C1) are provided wherein the compounds are of the formula (C1i)-(C1r) except that, instead of R¹ of formula (C1) being taken together with R^2a of formula (C1) to provide compounds of the formula (C1i)-(C1r), R^2a and R^3a are taken together to form an ethylene moiety or a propylene moiety. In still a further embodiment, compounds of the formula (C1) are provided wherein the compounds are of the formula (C1i)-(C1r) except that, instead of R¹ of formula (C1) being taken together with R^2a of formula (C1) to provide compounds of the formula (C1i)-(C1r), R^2a and R⁴ are taken together to form a methylene moiety or an ethylene moiety. In yet another embodiment, compounds of the formula (C1) are provided wherein the compounds are of the formula (C1i)-(C1r) except that, instead of R¹ of formula (C1) being taken together with R^2a of formula (C1) to provide compounds of the formula (C1i)-(C1r), R^3a and R⁴ are taken together to form a propylene moiety or a butylene moiety. Variations detailed throughout, where applicable, apply to such formulae the same as if each and every variation were specifically and individually listed. Pharmaceutically acceptable salts of such formulae are also provided. Pharmaceutically acceptable salts of compounds of formulae (C1i)-(C1r) are also provided.

All variations referring to the formulae herein, such as formulae (C1-a)-(C1r), where applicable, may apply to formula (C2), the same as if each and every variation were specifically and individually listed.

In some embodiments, compounds of the formula (CIA) have structures of formulae (G1)-(G5):

wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

each R⁴ and R⁵ is independently H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^8c is H, OH or substituted or unsubstituted C₁-C₈ alkyl;

R^8d is H or substituted or unsubstituted C₁-C₈ alkyl, and the bond indicates the presence of either an E or Z double bond configuration;

Y is O or NR¹¹;

each R¹¹, R^12a and R^12b is independently H or substituted or unsubstituted C₁-C₈ alkyl;

each X¹, X³ and X⁴ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

provided that when the compound is of the formula (G5), D is other than unsubstituted phenyl.

In some embodiments, the compound is of the formula (G1). In some embodiments, wherein the compound is of the formula (G2). In some embodiments, the compound is of the formula (G3). In some embodiments, the compound is of the formula (G4). In some embodiments, the compound is of the formula (G5).

In another aspect, compounds of formulae (C3)-(C4) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^2a, R^2b, R^3a, R^3b, R^10a and R^10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

R⁴ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ and a vicinal R^8a, where present, are taken together to form a bond;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

each m, n, o and p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g and R^8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

• • or is taken together with a geminal R^8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, or is taken together with a geminal R^8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,
  • or is taken together with a vicinal R^8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,
  • or is taken together with a vicinal R^8(a-h) to form a bond provided when an R^8(a-h) is taken together with a vicinal R^8(a-h) to form a bond, the geminal R^8(a-h) is other than hydroxyl and thiol and thiol,
  • or is taken together with vicinal R⁴ to form a bond; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR⁹═CR^10aR^10b, wherein R⁹ is H or a substituted or unsubstituted C₁-C₈ alkyl and R^10a and R^10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety.

In a particular variation, compounds of formulae (C3) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶ and R^8(a-h), where present, and Q are defined as for formula (C3) and, where applicable, any variation thereof detailed herein. That is, variations of formula (C3) detailed throughout, where applicable, apply to formulae (C3a)-(C3e) the same as if each and every variation were specifically and individually listed for formulae (C3a)-(C3e). Pharmaceutically acceptable salts of compounds of formulae (C3a)-(C3e) are also provided.

In particular variation, compounds of formula (C3) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X², X³ and X⁴ are defined as for formula (C3) and, where applicable, any variation thereof detailed herein, n is 0-5, o is 0-4, p is 0-3, Z is NH, N—CH₃, O or S, and W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino. In one particular aspect of this variation, W is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one particular aspect of this variation, Z is S. Variations of formula (C3) detailed throughout, where applicable, apply equally to any of formulae (C3f)-(C3h), the same as if each and every variation were specifically and individually listed for formula (C3f)-(C3h). Pharmaceutically acceptable salts of compounds of formulae (C3f)-(C3h) are also provided.

All variations referring to the formulae herein, such as formulae (C3a)-(C3h), where applicable, may apply to formula (C4), the same as if each and every variation were specifically and individually listed.

In another aspect, compounds of formulae (D1)-(D2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^2a, where present, are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R⁴, where present, are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^4a, where present, are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each R², R^2a and R^2b, where present, is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^2a and R^2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R² and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^2a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R² and R^3a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^2a and R^3a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^2a and R⁴ are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R² and R^7a are taken together to form a bond;

each R^3a and R^3b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^3a and R^3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R^3a and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^3a and R² are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3a and R^2a are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^3a and R⁴ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety or R^3a and R^4a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

each R⁴ or R^4a, where present, is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^4a and R¹ are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R⁴ and R^2a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^4a and R^2a are taken together to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R⁴ and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^4a and R^3a are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ and R^7a are taken together to form a bond;

each R^5a and R^5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^5a and R^5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R^5a and R^7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R^5a and R^7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R^5a and R^7e are taken together to form a bond, or

when m-o are each 1, then R^5a and R^7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

Y¹ is CR^7aR^7b, NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^7cR^7d;

Y², where present, is CR^7cR^7d, NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^7aR^7b and Y³, where present, is CR^7eR^7f;

Y³, where present, is CR^7eR^7f, NR⁸, O, S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^7cR^7d and Y⁴, where present, is CR^7gR^7h;

Y⁴, where present, is CR^7gR^7h, NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^7eR^7f;

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^7a and R^7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7a and R^7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7a and R^7c, where present, are taken together to form a bond, or R^7a and R² are taken together to form a bond, or R^7a and R⁴ are taken together to form a bond;

each R^7c and R^7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7c and R^7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7c and R^7a, where present, are taken together to form a bond, or R^7c and R^7e are taken together to form a bond;

each R^7e and R^7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7e and R^7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7e and R^7c are taken together to form a bond, or R^7e and R^7g, where present, are taken together to form a bond;

each R^7g and R^7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7g and R^7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or

R^7g and R^7e are taken together to form a bond, or R^7g and R^5a are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In one variation, the compound is of the formula (D2) where m-o are each 0, provided that the compound is other than cis-4-ethyl-2,3,3a,4-tetrahydro-3-(phenylmethyl)benzo[b]pyrido[2,3,4-gh]pyrrolizin-5(1H)-one and 1,2,3,3a,4,5-hexahydro-8-methoxy-4,4-dimethylbenzo[b]pyrido[2,3,4-gh]pyrrolizine.

In another variation, the compound is of the formula (D2) where m-o are each 0, provided that (i) when each X¹, X², X³ and X⁴ is CH, each R², R^3a, R^3b, R^4a and R^4b is H, R^5a and R^5b are taken together with the carbon to which they are attached to form a carbonyl moiety, and Y¹ is CR^7aR^7b where one of R^7a and R^7b is ethyl and the other is hydrogen, R¹ is other than benzyl, and (ii) when each X¹, X² and X⁴ is CH, X³ is CR⁶ where R⁶ is methoxy, CH, each R², R^3a, R^3b, R^4a, R^4b, R^5a and R^5b is H, and Y¹ is CR^7aR^7b where each R^7a and R^7b is methyl, R¹ is other than hydrogen.

In one variation, the compound is of the formula (D1) where m is 1 and n-o are each 0, provided that the compound is other than 1,2,3,3a,5,6-hexahydro-4H-indolo[3,2,1-ij][1,6]naphthyridin-4-one.

In one variation, the compound is of the formula (D1) where m is 1 and n-o are each 0, provided that when each X¹, X², X³ and X⁴ is CH, each R^2a, R^2b, R^3a, R^3b, R⁴, R^5a and R^5b is H, Y¹ is carbonyl and Y² is CH₂, R¹ is other than hydrogen.

In one variation, the compound is of the formula (D2) where m is 1 and n-o are each 0, wherein R¹, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², X³, X⁴, Y¹ and Y² are as defined for formula (D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶.

In another variation, the compound is of the formula (D2) where m is 1 and n-o are each 0, wherein R¹, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², X³, X⁴, Y¹ and Y² are as defined for formula (D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶, and when Y¹ is CR^7aR^7b and Y² is CR^7cR^7d, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is a group containing a cyclic moiety. In one such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is a C₁-C₈ alkyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In yet another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is a C₂-C₈ alkenyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl.

In one variation, the compound is of the formula (D2) where m-n are each 1 and n is 0, wherein R¹, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², X³, X⁴, X¹, Y² and Y³ are as defined for formula (D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶.

In another variation, the compound is of the formula (D2) where m-n are each 1 and n is 0, wherein R, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², X³, X⁴, Y¹, Y² and Y³ are as defined for formula (D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶, and when Y¹ is CR^7aR^7b and Y² is CR^7cR^7d, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is a group containing a cyclic moiety. In one such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is a C₁-C₈ alkyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In yet another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c and R^7d is a C₂-C₈ alkenyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl.

In another variation, the compound is of the formula (D2) where m-n are each 1 and n is 0, wherein R, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², X³, X⁴, Y¹, Y² and Y³ are as defined for formula (D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶, and when Y¹ is CR^7aR^7b, Y² is CR^7cR^7d and Y³ is CR^7eR^7f at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e and R^7f is a group containing a cyclic moiety. In one such variation, at least one of R^5a, R^5b, R^7a, R^7b R^7c, R^7d, R^7e and R^7f is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e and R^7f is a C₁-C₈ alkyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In yet another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e and R^7f is a C₂-C₈ alkenyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl.

In one variation, the compound is of the formula (D2) where m-o are each 1, wherein R¹, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², X³, X⁴, Y¹, Y², Y³ and Y⁴ are as defined for formula (D2), provided when Y¹ is CR^7aR^7b, Y² is CR^7cR^7d, Y³ is CR^7eR^7f and Y⁴ is CR^7gR^7h at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e, R^7f, R^7g and R^7h is a group containing a cyclic moiety. In one such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e, R^7f, R^7g and R^7h is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c, R^7d, R^7e, R^7f, R^7g and R^7h is a C₁-C₈ alkyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl. In yet another such variation, at least one of R^5a, R^5b, R^7a, R^7b, R^7c R^7d, R^7e, R^7f, R^7g and R^7h is a C₂-C₈ alkenyl substituted with a group selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl.

In another variation, the compound is of the formula (D2) where m-o are each 1, wherein R¹, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, X¹, X², X³, X⁴, Y¹, Y², Y³ and Y⁴ are as defined for formula (D2), provided when Y¹ is CR^7aR^7b, Y² is CR^7cR^7d, Y³ is CR^7eR^7f and Y⁴ is CR^7gR^7h at least one of X¹, X², X³ and X⁴ is N or CR⁶ and R^5a and R^5b are not taken together with the carbon to which they are attached to form a carbonyl moiety.

In specific variations, compounds of the formula (D1) have the structure:

or a salt or solvate thereof; wherein R¹, R^2a, R^2bR^3a, R^3bR^4a, R^4b, R^5a, R^5b, R⁶, R^7(a-h), X¹, X², X³, X⁴, Y¹, Y², Y³ and Y⁴, where present, are defined as for formula (D1) and, where applicable, any variation thereof detailed herein. That is, variations of formula (D1) detailed throughout, where applicable, apply to formulae (D1a)-(D1bm) the same as if each and every variation were specifically and individually listed for formulae (D1a)-(D1bm). Pharmaceutically acceptable salts of compounds of formulae (D1a)-(D1bm) are also provided.

All variations referring to the formulae herein, such as formulae (D1a)-(D1bm), where applicable, may apply to formula (D2), the same as if each and every variation were specifically and individually listed.

In another aspect, compounds of formulae (D3)-(D4) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^2a, R^2b, R^3a, R^3b, R^10a and R^10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

R⁴ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ and R^7a are taken together to form a bond;

each R^5a and R^5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^5a and R^5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R^5a and R^7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R^5a and R^7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R^5a and R^7e are taken together to form a bond, or

when m-o are each 1, then R^5a and R^7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

Y¹ is CR^7aR^7b, NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^7cR^7d;

Y², where present, is CR^7cR^7d, NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^7aR^7b and Y³, where present, is CR^7eR^7f;

Y³, where present, is CR^7eR^7f, NR⁸, O, S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^7cR^7d and Y⁴, where present, is CR^7gR^7h;

Y⁴, where present, is CR^7gR^7h, NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^7eR^7f;

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^7a and R^7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7a and R^7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7a and R^7c, where present, are taken together to form a bond, or R^7a and R⁴ are taken together to form a bond;

each R^7c and R^7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7c and R^7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7c and R^7a, where present, are taken together to form a bond, or R^7c and R^7e are taken together to form a bond;

each R^7e and R^7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7e and R^7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7e and R^7c are taken together to form a bond, or R^7e and R^7g, where present, are taken together to form a bond;

each R^7g and R^7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^7g and R^7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R^7g and R^7e are taken together to form a bond, or R^7g and R^5a are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In particular variation, compounds of formulae (D3) have the structure:

or a salt or solvate thereof; wherein R¹, R^5a, R^5b, R⁶, Y¹, Y², Y³ and Y⁴, where present, are defined as for formulae (D3) and, where applicable, any variation thereof detailed herein. That is, variations of formulae (D3) detailed throughout, where applicable, apply to formulae (D3a)-(D3d) the same as if each and every variation were specifically and individually listed for formulae (D3a)-(D3d). Pharmaceutically acceptable salts of compounds of formulae (D3a)-(D3d) are also provided.

All variations referring to the formulae herein, such as formulae (D3a)-(D3d), where applicable, may apply to formula (D4), the same as if each and every variation were specifically and individually listed.

In one variation of formulae (A1)-(A4) or (B1)-(B2), or any variation therefrom, at least one of X¹, X² and X³ is N. In another variation, one of X¹, X² and X³ is N. In one variation, X¹ is N and each X² and X³ is independently CH or CR⁶. In another variation, X² is N and each X¹ and X³ is independently CH or CR⁶. In yet another variation, X³ is N and each X¹ and X² is independently CH or CR⁶. In another variation, two of X¹, X² and X³ is N. In one variation, each X¹ and X³ is N and X² is CH or CR⁶.

In another variation of formulae (C1)-(C4) or (D1)-(D4), or any variation therefrom, at least one of X¹, X², X³ and X⁴ is N. In another variation, one of X¹, X² and X³ is N. In one variation, X¹ is N and each X², X³ and X⁴ is independently CH or CR⁶. In another variation, X² is N and each X¹, X³ and X⁴ is independently CH or CR⁶. In yet another variation, X³ is N and each X¹, X² and X⁴ is independently CH or CR⁶. In yet another variation, X⁴ is N and each X¹, X² and X³ is independently CH or CR⁶. In another variation, two of X¹, X², X³ and X⁴ is N. In one variation, each X¹ and X³ is N, and X² and X⁴ is CH or CR⁶. In another variation, each X² and X⁴ is N, and X¹ and X³ is CH or CR⁶. In another variation, each X¹ and X⁴ is N, and X² and X³ is CH or CR⁶.

In one variation of formulae (A1)-(A4) or (C1)-(C4), the chain comprising R^8a, R^8b R^8c, R^8d, R^8e, R^8f, R^8g, R^8h and Q is selected from the following structures:

or a salt or solvate thereof, wherein R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g, R^8h and Q are as defined herein and ring A comprises a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl group.

In another variation of formulae (A1)-(A4) or (C1)-(C4), the chain comprising R^8a, R^8b R^8c, R^8d, R^8e, R^8f, R^8g, R^8h and Q is selected from the following structures:

or a salt or solvate thereof, wherein R^8a, R^8b, R^8c, R^8d, R^8e, R^8f, R^8g, R^8h and Q are as defined herein and ring A comprises a substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl group. In a particular variation, when o and p are each 0, the chain comprising R^8a, R^8b, R^8c, R^8d and Q is selected from the following structures:

In a particular variation, where ring A depicted above comprises a substituted or unsubstituted C₃-C₈ cycloalkenyl, the double-bond of the cycloalkenyl ring is at a position other than in the linear chain. For example, if the carbon atoms bearing R^8a and R^8c are part of a substituted or unsubstituted C₃-C₈ cycloalkenyl ring, e.g., ring A depicted above, then the carbon atoms bearing R^8a and R^8c are connected by a single bond.

In certain embodiments, compounds are provided wherein R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. In specific embodiments, R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In more specific embodiments, R¹ is an unsubstituted C₁-C₈ alkyl such as methyl and cyclopropyl.

In certain embodiments, compounds are provided where R¹ is selected from the following moieties:

In certain compounds described herein, each R², R^2a and R^2b, where present, is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^2a and R^2b are taken together to form a carbonyl moiety. In specific embodiments, each R^2a and R^2b is independently H or fluoro. In another specific embodiment, R^2a and R^2b are both H. In a further specific embodiment, R^2a and R^2b are both H and R^3a and R^3b are both H.

In certain compounds described herein, each R^3a and R^3b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^3a and R^3b are taken together to form a carbonyl moiety. In specific embodiments, each R^3a and R^3b is independently H, methyl, fluoro or R^3a and R^3b are taken together to form a carbonyl moiety. In a specific embodiment, R^3a and R^3b are both H.

In certain compounds, each R⁴, R^4a and R^4b, where present, is independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^4a and R^4b are taken together to form a carbonyl moiety. In specific embodiments, each R^4a and R^4b is independently H, halo, hydroxyl or methyl or R^4a and R^4b are taken together to form a carbonyl moiety. In another specific embodiment, R^4a and R^4b are both H. In a further specific embodiment, R^4a and R^4b are both H and R^2a, R^2b, R^3a and R^3b are each H.

In certain compounds described herein, each R^10a and R^10b is independently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^10a and R^10b are taken together to form a carbonyl moiety. In specific embodiments, each R^10a and R^10b is independently H, methyl, fluoro or R^10a and R^10b are taken together to form a carbonyl moiety. In a specific embodiment, R^10a and R^10b are both H.

In certain compounds, each X¹, X², X³ and X⁴, where present, is independently N, CH or CR⁶. In certain embodiments, each X¹, X², X³ and X⁴, where present, is CH or CR⁶, such that the ring comprising X¹, X², X³ and X⁴, where present, is an optionally substituted phenyl ring. In specific embodiments, X² is CR⁶ where R⁶ is halo or alkyl and X¹ and X³ are each CH. In other embodiments, one of X¹, X², X³ and X⁴ is N, and the others are CH or CR⁶, such that the ring comprising X¹, X², X³ and X⁴ is an optionally substituted pyridine ring. In further embodiments, two of X¹, X², X³ and X⁴ are N, and the other is CH or CR⁶, such that the ring comprising X¹, X², X³ and X⁴ is an optionally substituted pyrimidine or pyrazine ring.

In certain compounds, each R⁶, where present, is independently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl. In one variation, at least one of X¹-X³ is CR⁶ where R⁶ is halo. In a particular variation, one of X¹-X³ is CR⁶ where R⁶ is chloro and the others are CH. In a specific variation, X¹ and X³ are each CH and X² is CR⁶ where R⁶ is chloro.

In certain embodiments, each R⁶, where present, is independently hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, alkylsulfonylamino or acyl. In further embodiments, each R⁶, where present, is independently hydroxyl, halo, C₁-C₄ perhaloalkyl, substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C₁-C₄ alkoxy; or in still a further variation, each R⁶, where present, is independently halo, unsubstituted C₁-C₄ alkyl or C₁-C₄ perhaloalkyl.

In specific embodiments, the ring comprising X¹, X², X³ and X⁴, where present, is a phenyl, pyridyl, pyrimidinyl or pyrazinyl ring, optionally substituted with 0-3 R⁶ groups (i.e., (R⁶)_n where n is 0, 1, 2 or 3). In some such embodiments, n is 1, 2 or 3 and each R⁶ is independently halo, methyl or CF₃.

In compounds of formulae (B1-B4) and (D1-D4), and variations thereof, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino. In one variation, compounds are provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted or a unsubstituted heterocyclyl. In certain embodiments, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl. In some such embodiments, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted phenyl, pyridyl or pyrimidinyl ring. When at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is substituted, it is frequently substituted with from 1-3 substituents selected from group consisting of halo, C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, and C₁-C₄ alkoxy.

In a particular variation, compounds of formulae (B1-B4) and (D1-D4), and variations thereof, have at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted heteroaryl, a monosubstituted aryl group substituted with a chloro or alkyl group or a di- or tri-substituted aryl moiety. For instance, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, in one variation is selected from the group consisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl and pyrimidinyl. In one aspect, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted pyridyl such as 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl.

In some embodiments, R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl; each R^2a and R^2b is independently H, methyl, fluoro or R^3a and R^3b are taken together to form a carbonyl moiety; each R^4a and R^4b is independently H or fluoro; and each R^3a and R^3b is independently H, halo, hydroxyl or methyl or R^2a and R^2b are taken together to form a carbonyl moiety. In particular variations, R¹ is an unsubstituted C₁-C₈ alkyl and R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are each H. In still a further variation, R¹ is an unsubstituted C₁-C₈ alkyl, R^2a, R^2b, R^3a, R^3b R^4a and R^4b are each H and at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is selected from the group consisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl and pyrimidinyl. In still a further variation, R¹ is an unsubstituted C₁-C₈ alkyl, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are each H and X² is CR⁶ where R⁶ is chloro. In yet a further variation, R¹ is an unsubstituted C₁-C₈ alkyl, R^2a, R^2b R^3a, R^3b, R^4a and R^4b are each H, X² is CR⁶ where R⁶ is chloro and at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted aryl or a substituted or substituted heteroaryl. In one such variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted phenyl.

In certain embodiments, compounds of formulae (A1)-(A4) or (C1)-(C4), and variations thereof, are provided where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino. In one variation, compounds are provided where Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl or substituted or a unsubstituted heterocyclyl. In certain embodiments, Q is a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl. In some such embodiments, Q is a substituted or unsubstituted phenyl, pyridyl or pyrimidinyl ring. When Q is substituted, it is frequently substituted with from 1-3 substituents selected from group consisting of halo, C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, and C₁-C₄ alkoxy.

In a particular variation of compounds of formulae (A1)-(A4) or (C1)-(C4), and variations thereof, Q is a substituted heteroaryl, a mono-substituted aryl group substituted with a chloro or alkyl group or a di- or tri-substituted aryl moiety. For instance, each Q in one variation is independently selected from the group consisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl and pyrimidinyl. In one aspect, Q is a substituted pyridyl such as 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl.

In particular embodiments, each X¹, X², X³ and X⁴, where present, is CH or CR⁶. In other embodiments, at least one of X¹, X², X³ and X⁴, where present, is N. Another variation provides a compound where at least two of X¹, X², X³ and X⁴, where present, are N. A further variation provides a compound where two of X¹, X², X³ and X⁴, where present, are N and one of X¹, X², X³ and X⁴, where present, is CH or CR⁶. Compounds where one of X¹, X², X³ and X⁴, where present, is N and two of X¹, X², X³ and X⁴, where present, are CH or CR⁶ are also embraced by this invention.

In one variation, compounds of formulae (A1)-(A4) and (B1)-(B4), and variations thereof, are provided wherein the ring comprising X¹, X² and X³ is an aromatic moiety selected from the following structures:

where each R⁶ is as defined. In a particular variation, each R⁶ is independently hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or acyl. In a further variation, each R⁶ is independently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, or C₁-C₄ alkoxy.

In a further variation, compounds of formulae (A1)-(A4) and (B1)-(B4), and variations thereof, are provided, wherein the ring comprising X¹, X² and X³ is an aromatic moiety selected from the following structures:

wherein R⁶ is as defined herein; or in a particular variation, where R⁶ is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or acyl; or in still a further variation, where each R⁶ is independently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, or C₁-C₄ alkoxy.

In a further variation, compounds of formulae (A1)-(A4) and (B1)-(B4), and variations thereof, are provided wherein the ring comprising X¹, X² and X³ is an aromatic moiety selected from the following structures:

In another variation, compounds of formulae (C1)-(C4) and (D1)-(D4), and variations thereof, are provided wherein the ring comprising X¹, X², X³, and X⁴ is an aromatic moiety selected from the following structures:

where each R⁶ is as defined. In a particular variation, each R⁶ is independently hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or acyl. In a further variation, each R⁶ is independently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, or C₁-C₄ alkoxy.

In a further variation, of formulae (C1)-(C4) and (D1)-(D4), and variations thereof, are provided, wherein the ring comprising X¹, X², X³ and X⁴ is an aromatic moiety selected from the following structures:

wherein R⁶ is as defined herein; or in a particular variation, where R⁶ is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or amino, alkylsulfonylamino or acyl; or in still a further variation, where each R⁶ is independently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, or C₁-C₄ alkoxy.

In a further variation, compounds of formulae (C1)-(C4) and (D1)-(D4), and variations thereof, are provided wherein the ring comprising X¹, X², X³ and X⁴ is an aromatic moiety selected from the following structures:

Any formula detailed herein, where applicable, may in one variation have X¹, X², X³ and X⁴, where present, taken together to provide an aromatic moiety detailed herein above. It is understood that by “where applicable” it is intended that in one variation such X¹, X², X³ and X⁴ groups are taken together to provide a moiety hereinabove if the formula encompasses such a structure. For example, if a given formula does not encompass structures wherein X¹, X², X³ and X⁴ groups are taken together provide a pyridyl moiety, then a pyridyl moiety as detailed hereinabove is not applicable to that particular formula, but remains applicable to formulae that do encompass structures where X¹, X², X³ and X⁴ groups are taken together provide a pyridyl moiety.

In another embodiment, a compound of the invention is provided, wherein X¹-X⁴, where present, are as defined or as detailed in any variation herein, where R¹ is H, substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl. In a further embodiment, a compound of the invention is provided, wherein X¹-X⁴ are as defined or as detailed in any variation herein, where R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl. In a particular variation, a compound of the invention is provided, wherein X¹-X⁴ are as defined or as detailed in any variation herein, where R¹ is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

When any carbon of the preceding formulae bearing R^2a and R^2b, or R^3a and R^3b, or R^4a and R^4b, or R^10a and R^10b is optically active, it may be in the (R)- or (S)-configuration and compositions comprising substantially pure (R) or (S) compound or mixtures thereof in any amount are embraced by this invention.

In one variation, compounds of formulae (A1) and (B1), and variations thereof, are provided wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b is a moiety selected from the following structures:

wherein R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are as defined, and p is 1 or 2.

In another variation, compounds of formulae (A2) and (B2), and variations thereof, are provided wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b is a moiety selected from the following structures:

wherein R¹, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are as defined, and p is 1 or 2.

In another variation, compounds of formulae (A1) and (B1), and variations thereof, are provided wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b is a moiety selected from the following structures:

In another variation, compounds of formulae (A2) and (B2), and variations thereof, are provided wherein the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b is a moiety selected from the following structures:

In any one of the variations of compounds of the formulae described herein, all stereoisomers are intended. For example, the ring can be either

Where more than one stereocenter is present, it is understood that all such stereoisomers are intended. For example, a compound having two stereocenters may be present in the (S),(S); (S),(R); (R),(R); and (R),(S) forms. Compositions comprising a single stereoisomer or mixtures of more than one stereoisomer are also intended. Compositions comprising a mixture of stereoisomers in any ratio are embraced, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.

In some embodiments of formulae (A1) and (B1), and variations thereof, are provided, the ring comprising N, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b is a moiety selected from the following structures:

where R¹ in the structures above is as defined or as detailed in any particular variation detailed herein. In some embodiments, the ring is of the formula:

where R¹ is as detailed in any particular variation detailed herein. Any formula detailed herein, where applicable, may in one variation have a ring according to the structures above.

Compounds according to formulae (A1)-(A4) or (C1)-(C4), or any variation thereof, in one variation are provided where m, n, o, p, and R^8(a-h), if present and where applicable, are taken together to form a moiety selected from the group consisting of the structures:

When the above structures are applied to formulae (A1)-(A4) or (C1)-(C4), or any variation thereof, herein, it is understood that m, n, o, p and R^8(a-h), where applicable, are taken together to form the foregoing moieties, including but not limited to, the structures of this paragraph. Likewise, any formula detailed herein, where applicable, may in one variation have m, n, o, p and R^8(a-h), if present, taken together to form a moiety as detailed herein above, including but not limited to, the structures of this paragraph. It is understood that by “where applicable” it is intended that in one variation such m, n, o, p and R^8(a-h) groups, if present, are taken together to provide a moiety hereinabove if the formula encompasses such a structure. For example, if a given formula does not encompass structures wherein m, n, o, p and R^8(a-h) groups, if present, are taken together to provide a —CH₂CH₂— moiety, then a —CH₂CH₂— moiety as detailed hereinabove is not applicable to that particular formula, but remains applicable to formulae that do encompass structures where m, n, o, p and R^8(a-h) groups, if present, are taken together to provide a —CH₂CH₂— moiety.

In one aspect, at least one of R^8(a-h) is a C₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety.

Compounds according to formulae (A1)-(A4) or (C1)-(C4), or any variation thereof, where applicable, in one variation are provided where one or more of R^8(a-h) and the carbon to which it is attached, together with a vicinal R⁸ and the carbon to which it is attached, form a moiety selected from the group consisting of the structures, each of which may be optionally substituted, where each R⁸ is independently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy or carbonylalkoxy:

In another variation, any double bond, if present in the cycloalkenyl ring, may also be present at any location in the ring, where chemically feasible, as exemplified above for the cyclopropenyl moiety.

In certain compounds where applicable in one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, which may be but is not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In one variation, a compound of the invention is provided, where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted phenyl or pyridyl group. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a phenyl or pyridyl group substituted with at least one methyl, trifluoromethyl, methoxy or halo substituent. In another variation, a compound of the invention is provided, where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C₁-C₄ alkyl, C₁-C₄ alkoxy, halo or C₁-C₄ perhaloalkyl moiety.

In still another variation, compounds are provided, where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted C₃-C₈ cycloalkyl or a substituted or unsubstituted heterocyclyl. In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted C₃-C₈ cycloalkyl or a substituted or unsubstituted heterocyclyl. In yet another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl, CF₃, methoxy or halo group.

In one variation, compounds are provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an unsubstituted cycloalkyl or an unsubstituted heterocyclyl. In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an unsubstituted C₃-C₈ cycloalkyl or an unsubstituted heterocyclyl. In another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. In yet another variation, a compound of the invention is provided where at least one of R^5a, R^5b R^7(a-h) or Q, where present, is a substituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group. R^5a, R^5b, R^7(a-h) or Q, where present, groups may be attached to the parent structure at any available position on the R^5a, R^5b, R^7(a-h) or Q moiety. Thus, although specific attachment points for certain R^5a, R^5b, R^7(a-h) or Q moieties are depicted herein, it is understood that such R^5a, R^5b, R^7(a-h) or Q moieties, may also be connected to the parent structure at any available position. For example, if a monofluoro-phenyl is depicted herein, it is understood that each of the available mono-fluoro-phenyl moieties are intended, e.g., 2-fluoro-phenyl, 3-fluoro-phenyl and 4-fluoro-phenyl. It is also understood that any formula detailed herein, where applicable, may in one variation have a R^5a, R^5b, R^7(a-h) or Q, where present, moiety as detailed herein and below.

In still another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl (C₁-C₈), perhaloalkoxy (C₁-C₈), substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, the R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with no more than one R⁹ group. In another variation, the R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with only one R⁹ group. In one variation, the R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with two R⁹ groups. In a further variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is selected from the aromatic structures detailed where the residue has the moiety (R⁹)₀ such that the R^5a, R^5b, R^7(a-h) or Q either contains no R⁹ functionality or a moiety of the formula N—R⁹. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is selected from the aromatic structures detailed where the R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with no more than one R⁹ group. In another variation, the R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with only one R⁹ group. In one variation, the R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with two R⁹ groups. In a further variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is selected from the aromatic structures detailed where the residue has the moiety (R⁹)₀ such that the R^5a, R^5b, R^7(a-h) or Q, where present, either contains no R⁹ functionality or a moiety of the formula N—R⁹.

In another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety selected from the structures:

wherein R⁹ is connected to the R^5a, R^5b, R^7(a-h) or Q, where present, ortho or para to the position at which R^5a, R^5b, R^7(a-h) or Q, where present, is connected to the carbon bearing the R^5a, R^5b R^7(a-h) or Q, where present. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a structure of the formula

and R⁹ is connected to the R^5a, R^5b, R^7(a-h) or Q, where present, para to the position at which the R^5a, R^5b, R^7(a-h) or Q, where present, is connected to the carbon bearing the R^5a, R^5b, R^7(a-h) or Q, where present. In another particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a structure of the formula

where each R⁹ is independently alkyl, perhaloalkyl or halo.

In another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. In one variation, the R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with no more than one R⁹ group. In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is substituted with only one R⁹ group. In yet another variation, at least one of R^5a, R^5b R^7(a-h) or Q, where present, is substituted with two R⁹ groups. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is selected from the carbocyclic and heterocyclic structures detailed where the residue has the moiety (R⁹)₀ such that at least one of R^5a, R^5b, R^7(a-h) or Q, where present, either contains no R⁹ functionality or a moiety of the formula N—R⁹.

In any structure or variation detailed herein containing an R⁹ group, in one variation, each R⁹ is independently a substituted or unsubstituted C₁-C₄ alkyl, halo, trifluoromethyl or hydroxyl. In another variation, each R⁹ is independently methyl, —CH₂OH, isopropyl, halo, trifluoromethyl or hydroxyl.

In another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety selected from the structures:

In another variation, a compound of the invention is provided where at least one of R^5a R^5b, R^7(a-h) or Q, where present, is a moiety selected from the structures:

In another variation, a compound of the invention is provided where at least one of R^5a R^5b, R^7(a-h) or Q, where present, is a moiety selected from the structures:

In yet another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety selected from the structures:

In any of the variations described herein for R^5a, R^5b, R^7(a-h), or Q, where present, only one point of attachment of each moiety to the parent structure may be depicted, however it is understood that the moiety may be attached to the parent structure at any position, where chemically feasible.

In another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino moiety. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an unsubstituted amino. In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted amino of the formula —N(C₁-C₈ alkyl)₂ such as the moiety —N(Me)₂ or —N(CH₃)(CH₂CH₃). In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted amino of the formula —N(H)(cycloalkyl or substituted cycloalkyl), such as a moiety of the formula:

In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is independently a substituted amino of the formula —N(H)(aryl or substituted aryl), such as a moiety of the formula:

The invention also embraces compounds where at least one of R^5a, R^5b, R^7(a-h) Or Q, where present, is an aminoacyl moiety. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an aminoacyl group where at least one of R_a and R_b is H, such as when at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is of the formula —NHC(O)R_b. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an aminoacyl moiety selected from the group consisting of: —NHC(O)-heterocyclyl, —NHC(O)— substituted heterocyclyl, —NHC(O)-alkyl, —NHC(O)-cycloalkyl, —NHC(O)-aralkyl and —NHC(O)-substituted aryl. In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an aminoacyl moiety selected from the group consisting of: —NHC(O)—C₅-C₇ heterocyclyl, —NHC(O)—C₁-C₆ alkyl, —NHC(O)—C₃-C₇ cycloalkyl, —NHC(O)—C₁-C₃ aralkyl and —NHC(O)-substituted phenyl. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety of the formula:

In one variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is acyloxy.

In one variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a carbonylalkoxy moiety. In one variation, at least one of R^5a R^5b, R^7(a-h) or Q, where present, is a carbonylalkoxy moiety of the formula —C(O)—O—R where R is H, alkyl, substituted alkyl or alkaryl. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a carbonylalkoxy moiety of the formula —C(O)—O—C₁-C₆ alkyl. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a carbonylalkoxy moiety of the formula —C(O)—O—C₂H₅. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a carbonylalkoxy moiety selected from the group consisting of: —C(O)—O—C₁-C₁₀alkyl, —C(O)—O—C₁-C₃alkaryl, —C(O)—O—C₁-C₃substituted alkyl and —C(O)—OH. In another variation, R^5a, R^5b R^7(a-h) or Q, where present, is —C(O)—O—C₁-C₆alkyl. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety of the formula:

In another variation, a compound of the invention is provided where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an aminocarbonylalkoxy moiety. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an aminocarbonylalkoxy moiety of the formula —NHC(O)—O—R_b. In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an aminocarbonylalkoxy moiety of the formula —NHC(O)—O—R_b where R_b is a substituted alkyl group. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety of the formula —NH—C(O)—O—CH₂—CCl₃.

The invention also embraces compounds where at least one of R^5a, R^5b, R^7(a-h) Or Q, where present, is an acylamino moiety. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an acylamino group where at least one of R_a and R_b is H, such as when R^5a R^5b, R^7(a-h) or Q, where present, is of the formula —C(O)N(H)(R_b). In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an acylamino group where both R_a and R_b are alkyl. In one variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an acylamino moiety selected from the group consisting of: —C(O)—N(H)(alkyl), —C(O)—N(alkyl)₂, —C(O)—N(H)(aralkyl) and —C(O)—N(H)(aryl). In another variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is an acylamino moiety selected from the group consisting of: —C(O)—N(H)₂, —C(O)—N(H)(C₁-C₈ alkyl), —C(O)—N(C₁-C₆ alkyl)₂ and —C(O)—N(H)(C₁-C₃aralkyl). In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a moiety of the formula:

In a further variation, a compound of the invention is provided where R¹ is an unsubstituted alkyl, R^2a, R^2b, R^3a, R^3b, R^4a and R^4b are each H, each X¹, X² and X³ and X⁴, where present, is independently N or CH, and at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted phenyl or pyridyl group. Where at least one of R^5a, R^5b R^7(a-h) or Q, where present, is a substituted phenyl or pyridyl group, in one variation it is substituted with at least one methyl or halo group.

In yet a further variation, a compound of the invention is provided where R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl; each R^2a and R^2b is independently H, unsubstituted C₁-C₈ alkyl or halo; each R^3a and R^3b is independently H or halo; each X¹, X² and X³ and X⁴, where present, is CH or CR⁶, where R⁶ is as defined or as detailed in a particular variation, R⁶ is halo, pyridyl, methyl or trifluoromethyl; R^4a and R^4b are both H, and at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, including but not limited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In a particular variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with at least one substituted or unsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety. In one variation, a compound of the variation detailed herein is provided wherein R¹ is propylate, methyl, ethyl, cyclopropyl, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy-1-methylcycloprop-2-yl, or 1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In still a further variation, a compound of the invention is provided where R¹ is a substituted or unsubstituted C₁-C₈ alkyl; each R^2a, R^2b, R^3a and R^3b is independently H or halo; each R⁶ is independently halo, C₁-C₈ perhaloalkyl, substituted or a unsubstituted C₁-C₈ alkyl; and at least one of R^5a, R^5b, R^7(a-h) or Q, where present, is a substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. The invention also embraces a compound where R¹ is a methyl; at least one of X¹, X² and X³ and X⁴, where present, is CR⁶, and each R⁶ is independently halo, methyl or trifluoromethyl. The invention embraces compounds where at least one of R^5a, R^5b, R^7(a-h) or Q, where present, in any variation detailed is substituted with at least one carbonyl, hydroxymethyl, methyl or hydroxyl group, to the extent such substituent makes chemical sense.

In a particular variation, a compound is provided where R¹ is a substituted or unsubstituted C₁-C₈ alkyl; each R^2a and R^2b is independently H, a substituted or unsubstituted C₁-C₈ alkyl or R^2a and R^2b are taken together to form a carbonyl moiety; R^3a and R^3b are both H; each R^4a and R^4b is independently H, halo, a substituted or unsubstituted C₁-C₈ alkyl, hydroxyl, alkoxy or R^4a and R^4b are taken together to form a carbonyl moiety, provided that at least one of R^4a and R^4b is other than H. In one aspect of this variation, at least one of R^5a, R^5b, R^7(a-h) or Q, where present, may be a substituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. In another aspect of this variation, at least one of R^5a R^5b, R^7(a-h) or Q, where present, is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with at least one methyl or halo group. In yet another aspect of this variation, each X¹, X² and X³ and X⁴, where present, is independently CH or CR⁶ and each R⁶ is independently halo or methyl.

In a particular variation, a compound is provided wherein R¹, R^2a, R^2b, R^3a, R^3b, R^10a R^10b, R^11a and R^11b are taken together to form a ring selected from the structures:

where R¹ in the structures above is as defined herein.

In one embodiment, the invention relates to compounds of Tables 1-4, and uses thereof.

In another embodiment, the invention relates to Compound nos. A1 to A160, B1 to B242, C1 to C136 and D1 to D266, and uses thereof.

In another embodiment, the invention relates to Compound nos. A1 to A18, A43 to A44, B1 to B16, B156 to B165, B210 to B211, C43 to C48, and D1 to D12, and uses thereof.

The embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable.

Representative examples of compounds detailed herein, including intermediates and final compounds according to the invention are depicted in the tables below. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.

The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds of the invention are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.

Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. For example, when a 2-hydroxypyridyl moiety is depicted, the corresponding 2-pyridone tautomer is also intended. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.

Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. Taking compound 1 as an example, a composition of substantially pure compound 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound 1 or a salt thereof. In one variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity. In yet other variations, the composition of “substantially pure” compound contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.

In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

Kits comprising a compound of the invention, or a salt or solvate thereof, and suitable packaging are provided. In one embodiment, a kit further comprises instructions for use. In one aspect, a kit comprises a compound of the invention, or a salt or solvate thereof, and instructions for use of the compounds in the treatment of a disease or condition for which a reduction in blood pressure and/or promoting renal blood flow and/or inhibiting or decreasing sodium reabsorption is expected to be or is beneficial.

Articles of manufacture comprising a compound of the invention, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule and the like.

In one aspect, a compounds detailed herein as provided herein exhibits the ability to cross the blood-brain barrier. In another aspect, a compounds detailed herein as provided herein is not able to cross the blood-brain barrier. In one aspect, a compounds detailed herein as provided herein exerts its therapeutic effect in the brain only. In one aspect, a compounds detailed herein as provided herein exerts its therapeutic effect in the periphery only. In one aspect, a compounds detailed herein as provided herein exerts its therapeutic effect both in the brain and peripherally. In some embodiments, the adrenergic receptor α_2B antagonist is a selective adrenergic receptor α_2B antagonist. In some embodiments, the adrenergic receptor α_2B antagonist also exhibits adrenergic receptor α_2A antagonist and/or inverse agonist activity.

Blood brain barrier permeability can be measured in rodents or dog by administering the compound orally or intravenously, recovering a blood and brain tissue sample at different time points and comparing how much compound is in each sample. Blood fraction is typically processed to plasma for determination of compound content. Brain exposure can be described from the ratio of brain to plasma levels of drug. In one variation, a compound that poorly crosses the blood brain barrier has a brain to plasma ratio of compound of about 0.1 or less. In another variation, the compound has a brain to plasma ratio of about 0.2 or less, about 0.3 or less, about 0.4 or less, about 0.5 or less, about 0.8 or less, or about 1.0 or less.

Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration. In some settings, parenteral administration of an adrenergic receptor α_2B antagonists (e.g., selective adrenergic receptor α_2B antagonist) may be desired. For example, intra-renal delivery may offer treatment options for acute and chronic renal failure, end stage renal failure and acute decompensated congestive heart failure. Parenteral formulation may be preferred in the treatment of hypertensive urgency and emergency. In some embodiments, the adrenergic receptor α_2B antagonist is a selective adrenergic receptor α_2B antagonist. In some embodiments, the adrenergic receptor α_2B antagonist also exhibits adrenergic receptor α_2A antagonist and/or inverse agonist activity.

One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., reducing the blood pressure of an individual, promoting renal blood flow and/or decreasing or inhibiting sodium reabsorption.

Methods as provided herein may comprise administering to an individual a pharmacological composition that contains an effective amount of a compound and a pharmaceutically acceptable carrier. The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg.

The compound may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 20^th ed. (2000), which is incorporated herein by reference.

Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.

The compound may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.

Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided.

The invention further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a pharmacological composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for any one or more of the following uses: treating, preventing, and/or delaying the onset and/or development of hypertension and/or a disease or condition which is responsive, or expected to be responsive, to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption.

Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.

The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual.

The invention also provides compositions (including pharmacological compositions) as described herein for the use in treating, preventing, and/or delaying the onset and/or development of hypertension and/or a disease or condition which is responsive, or expected to be responsive, to (i) a reduction in an individual's blood pressure and/or (ii) an increase in renal blood flow and/or (iii) a decrease or inhibition of sodium reabsorption and other methods described herein.

Representative compounds of the invention are shown in Tables 1-4.

TABLE 1
Representative Compounds of the Invention
Compound
No. Structure
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
A30
A31
A32
A33
A34
A35
A36
A37
A38
A39
A40
A41
A42
A43
A44
A45
A46
A47
A48
A49
A50
A51
A52
A53
A54
A55
A56
A57
A58
A59
A60
A61
A62
A63
A64
A65
A66
A67
A68
A69
A70
A71
A72
A73
A74
A75
A76
A77
A78
A79
A80
A81
A82
A83
A84
A85
A86
A87
A88
A89
A90
A91
A92
A93
A94
A95
A96
A97
A98
A99
A100
A101
A102
A103
A104
A105
A106
A107
A108
A109
A110
A111
A112
A113
A114
A115
A116
A117
A118
A119
A120
A121
A122
A123
A124
A125
A126
A127
A128
A129
A130
A131
A132
A133
A134
A135
A136
A137
A138
A139
A140
A141
A142
A143
A144
A145
A146
A147
A148
A149
A150
A151
A152
A153
A154
A155
A156
A157
A158
A159
A160

TABLE 2
Representative Compounds of the Invention
Com-
pound
No. Structure
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
B22
B23
B24
B25
B26
B27
B28
B29
B30
B31
B32
B33
B34
B35
B36
B37
B38
B39
B40
B41
B42
B43
B44
B45
B46
B47
B48
B49
B50
B51
B52
B53
B54
B55
B56
B57
B58
B59
B60
B61
B62
B63
B64
B65
B66
B67
B68
B69
B70
B71
B72
B73
B74
B75
B76
B77
B78
B79
B80
B81
B82
B83
B84
B85
B86
B87
B88
B89
B90
B91
B92
B93
B94
B95
B96
B97
B98
B99
B100
B101
B102
B103
B104
B105
B106
B107
B108
B109
B110
B111
B112
B113
B114
B115
B116
B117
B118
B119
B120
B121
B122
B123
B124
B125
B126
B127
B128
B129
B130
B131
B132
B133
B134
B135
B136
B137
B138
B139
B140
B141
B142
B143
B144
B145
B146
B147
B148
B149
B150
B151
B152
B153
B154
B155
B156
B157
B158
B159
B160
B161
B162
B163
B164
B165
B166
B167
B168
B169
B170
B171
B172
B173
B174
B175
B176
B177
B178
B179
B180
B181
B182
B183
B184
B185
B186
B187
B188
B189
B190
B191
B192
B193
B194
B195
B196
B197
B198
B199
B200
B201
B202
B203
B204
B205
B206
B207
B208
B209
B210
B211
B212
B213
B214
B215
B216
B217
B218
B219
B220
B221
B222
B223
B224
B225
B226
B227
B228
B229
B230
B231
B232
B233
B234
B235
B236
B237
B238
B239
B240
B241
B242

TABLE 3
Representative Compounds of the Invention
Com-
pound
No. Structure
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
C25
C26
C27
C28
C29
C30
C31
C32
C33
C34
C35
C36
C37
C38
C39
C40
C41
C42
C43
C44
C45
C46
C47
C48
C49
C50
C51
C52
C53
C54
C55
C56
C57
C58
C59
C60
C61
C62
C63
C64
C65
C66
C67
C68
C69
C70
C71
C72
C73
C74
C75
C76
C77
C78
C79
C80
C81
C82
C83
C84
C85
C86
C87
C88
C89
C90
C91
C92
C93
C94
C95
C96
C97
C98
C99
C100
C101
C102
C103
C104
C105
C106
C107
C108
C109
C110
C111
C112
C113
C114
C115
C116
C117
C118
C119
C120
C121
C122
C123
C124
C125
C126
C127
C128
C129
C130
C131
C132
C133
C134
C135
C136

TABLE 4
Representative Compounds of the Invention
Com-
pound
No. Structure
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
D16
D17
D18
D19
D20
D21
D22
D23
D24
D25
D26
D27
D28
D29
D30
D31
D32
D33
D34
D35
D36
D37
D38
D39
D40
D41
D42
D43
D44
D45
D46
D47
D48
D49
D50
D51
D52
D53
D54
D55
D56
D57
D58
D59
D60
D61
D62
D63
D64
D65
D66
D67
D68
D69
D70
D71
D72
D73
D74
D75
D76
D77
D78
D79
D80
D81
D82
D83
D84
D85
D86
D87
D88
D89
D90
D91
D92
D93
D94
D95
D96
D97
D98
D99
D100
D101
D102
D103
D104
D105
D106
D107
D108
D109
D110
D111
D112
D113
D114
D115
D116
D117
D118
D119
D120
D121
D122
D123
D124
D125
D126
D127
D128
D129
D130
D131
D132
D133
D134
D135
D136
D137
D138
D139
D140
D141
D142
D143
D144
D145
D146
D147
D148
D149
D150
D151
D152
D153
D154
D155
D156
D157
D158
D159
D160
D161
D162
D163
D164
D165
D166
D167
D168
D169
D170
D171
D172
D173
D174
D175
D176
D177
D178
D179
D180
D181
D182
D183
D184
D185
D186
D187
D188
D189
D190
D191
D192
D193
D194
D195
D196
D197
D198
D199
D200
D201
D202
D203
D204
D205
D206
D207
D208
D209
D210
D211
D212
D213
D214
D215
D216
D217
D218
D219
D220
D221
D222
D223
D224
D225
D226
D227
D228
D229
D230
D231
D232
D233
D234
D235
D236
D237
D238
D239
D240
D241
D242
D243
D244
D245
D246
D247
D248
D249
D250
D251
D252
D253
D254
D255
D256
D257
D258
D259
D260
D261
D262
D263
D264
D265
D266

General Synthetic Methods

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

General Protocol for Chiral Preparative HPLC Separation of Racemic Compounds

For chiral separations, samples were dissolved in Methanol and Ethanol according to the solubility of sample and filtered through 0.22μ PTFE filters. The columns used were CHIRALPAK-AD; 20*250 mm, 10μ and CHIRALCEL-ODH; 20*250 mm, 5μ. A flow rate of 12 mL/min-17 mL/min was used according to the resolution. Alkanes such as n-Pentane, Hexane and Heptane (40%-95%) and alcohols such as Ethanol, Isopropyl alcohol and t-Butanol (5%-60%) were used as mobile phase. In some cases alcohol combinations i.e. (Ethanol+Methanol), (Ethanol+IPA), (IPA+Methanol), (t-Butanol+Methanol), (t-Butanol+Ethanol) were used instead of a single alcohol. Diethyl amine (up to 0.3%) was used as modifier in the mobile phase.

The following abbreviations are used herein: thin layer chromatography (TLC); hour (h); minute (min); second (sec); ethanol (EtOH); dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor (Rf); room temperature (RT).

General methods of preparing compounds according to the invention are depicted in exemplified methods below. Other compounds of the invention may be prepared by similar methods. Synthetic methods to provide similar intermediates have also been described in, for example, PCT Publication Nos. WO2009-055828, WO2009-094668, WO2009-120717, WO2009-120720, WO2009-038161, WO2009-038162 and WO2009-038164. Synthetic methods to provide azepino[4,5-b]indole intermediates have been described in PCT Publication No. WO-2009-051503. Synthetic methods to provide bicyclo pyrido[3,4-b]indoles have been described in PCT Publication No. WO2009-038163. The synthesis of Compound Nos. A1 to A160 has been described specifically in PCT Publication No. WO2011-103433. The synthesis of Compound Nos. B1 to B242 has been described specifically in PCT Publication No. WO2011-103460. The synthesis of Compound Nos. C1 to C136 has been described specifically in PCT Publication No. WO2011-103487. The synthesis of Compound Nos. D1 to D266 has been described specifically in PCT Publication No. WO2011-103485. The experimental details of each of these Applications are incorporated herein by reference.

Exemplified routes to synthesizing particular compounds of the invention are shown in the General Methods below.

General Method A1.

Step 1: Preparation of compound 1-B.

A solution of 4-chloro-2-bromophenyl hydrazine hydrochloride (15 g, 58 mmol) and 1-methylpiperidin-4-one (6.57 g, 58 mmol) in 7% H₂SO₄ in dioxane (150 mL) is stirred at 80° C. for 5 h. The progress of reaction is monitored by TLC. The reaction mixture is concentrated under reduced pressure to dryness. The residue is basified with aq. NaOH solution and extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which is purified by column chromatography (7% MeOH-DCM) to yield compound 1-B (7.6 g).

Step 2: Preparation of compound 1-C.

A stirred solution of 6-bromo-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1-B) (200 mg, 0.667 mmol) in DMF (2 mL) is cooled to −78° C., followed by addition of sodium hydride (20 mg, 0.800 mmol) and methyl iodide (2M in DMF, 0.3 mL, 0.60 mmol). The reaction mixture is stirred at −78° C. for 5 min. Ice-water is added into the reaction mixture and the mixture is then extracted with EtOAc (2×10 mL). The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which is purified by column chromatography using silica (100:200 mesh) and 0-4%

MeOH:DCM to yield compound 1-C (38 mg).

Step 3: Preparation of compound 1-D.

A mixture of 6-bromo-8-chloro-2,3,4,5-tetrahydro-2,5-dimethyl-1H-pyrido[4,3-b]indole (1-C) (210 mg, 0.670 mmol), copper(I)iodide (1.3 mg, 0.007 mmol), dichlorobis(triphenylphosphine) palladium(II) (24 mg, 0.034 mmol) is evacuated and back filled with nitrogen. Triethylamine (2.5 mL) is added, followed by dropwise addition of ethynyltriisopropylsilane (146 mg, 0.804 mmol). The reaction mixture is stirred at 85° C. overnight. Water is added into the reaction mixture and the mixture is then extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which is purified by column chromatography using silica (100:200 mesh) and 0-4% MeOH:DCM to yield compound 1-D (218 mg).

Step 4: Preparation of compound 1-E.

To an ice cooled stirred solution of 8-chloro-2,3,4,5-tetrahydro-6-(2-(triisopropylsilyl)ethynyl)-2,5-dimethyl-1H-pyrido[4,3-b]indole (1-D) (212 mg, 0.512 mmol) in dry THF (10 mL) is added tetrabutylammoniumfluoride (1M solution in THF, 1.638 mL, 1.638 mmol). The reaction mixture is allowed to warm to RT and stirring continued for 15 min. Water is added into the reaction mixture and the mixture is extracted with EtOAc (2×25 mL). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford compound 1-E (166 mg).

Step 5: Preparation of compound 1-F.

A mixture of 8-chloro-6-ethynyl-2,3,4,5-tetrahydro-2,5-dimethyl-1H-pyrido[4,3-b]indole (1-E) (166 mg, 0.642 mmol), 5-bromo-2-methylpyridine (132 mg, 0.770 mmol), dichlorobis(triphenyl phosphine)palladium (II) (23 mg, 0.032 mmol) and copper (I) iodide (1.1 mg, 0.006 mmol) is evacuated and back filled with nitrogen. Triethylamine (2 mL) is added dropwise under nitrogen atmosphere. The reaction mixture is stirred at 85° C. overnight. Triethylamine is evaporated under reduced pressure. The residue is dissolved in water (10 mL) and extracted with EtOAc (2×25 mL). The organic layer is washed with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which is purified by column chromatography using neutral alumina and 0-8% MeOH-EtOAc, followed by reverse phase HPLC to yield compound 1-F as the free base (16.23 mg).

General Method A2.

Step 1: Preparation of compound 2-B.

To a suspension of 2-chlorophenyl hydrazine hydrochloride (2-A) (19.7 g, 0.110 mol) in dioxane (190 mL) is dropwise added conc. H₂SO₄ (8 mL, 0.150 mol). After stirring for 10 min, N-methyl-4-piperidone (17.53 g, 0.154 mol) is added into the reaction mixture and stirring continued at RT for 20 min. The reaction mixture is then stirred at 80° C. for 4 h. The progress of reaction is monitored by TLC. The solvent is removed under reduced pressure and the pH of the residue adjusted to pH 8-9 by addition of saturated sodium bicarbonate solution. The aqueous layer is extracted with EtOAc (3×300 mL). The combined organic layer is washed with water, followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which is purified by re-crystallization (Ether/Hexane) to yield compound 2-B as a brown solid (7.5 g).

Step 2: Preparation of compound 2-C.

To a degassed mixture of 6-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2-B) (100 mg, 0.5 mmol), sodium tert-butoxide (576 mg, 6.0 mmol), palladium acetate (22.4 mg, 0.1 mmol) and 2,4 di-tert-butylphosphino-2′,4′,6′-triisopropyl biphenyl (63.0 mg, 0.15 mmol) is added dry toluene (2 mL). After stirring for 5 min, benzylmethylamine (0.09 mL, 0.7 mmol) is added to the reaction mixture, which is stirred at 100° C. for 16 h. The reaction mixture is filtered and the residue washed with EtOAc. The filtrate is concentrated under reduced pressure to afford crude material, which is purified by reverse phase HPLC to yield benzyl-methyl-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl)-amine (2-C) (50 mg).

General Method A3.

Alcohol compounds of type 3-C can be prepared from the bromo precursor 3-A by treatment with epoxide 3-B under standard Grignard or Grignard-cuprate coupling conditions known to those skilled in the art. Fluorination of 3-C with agents such as Diethylaminosulfur-trifluoride (DAST) provides the fluoro derivative 3-D. Alternatively, treatment of 3-A with alkene 3-E under Heck coupling conditions affords the styryl product of the type 3-F. Alternative coupling conditions including Stille and Suzuki, and the like, using corresponding reagents, will be familiar to those skilled in the art.

General Method B1.

Nitrile compound 1-A, if not commercially available, can be synthesized from precursors such as the halo, hydroxyl and/or ester compounds, using standard functional group conversion means known to those skilled in the art. Compound 1-A is subjected to a condensation reaction with aldehyde 1-B to produce alkene 1-C which is reduced to alkane intermediate 1-D. Hydrogenation of 1-D results in cyclization to the tetrahydroquinoline 1-E which, when subjected to nitrosation conditions, yields nitroso compound 1-F. Reduction of 1-F with zinc dust in the presence of acetone yields ylide 1-G which when heated with acid in the presence of piperidone 1-H, provides the desired final tetracyclic product 1-J.

General Method B2.

Aldehyde 2-A is subjected to Fischer-Indole synthesis conditions with hydrazine 2-B to give indole 2-C. Mild reduction of 2-C results in indoline 2-D. In an analogous fashion to the conversion of tetrahydroquinoline 1-E to tetracyclic compound 1-J, indoline 2-D is subjected to nitrosating conditions to give nitroso intermediate 2-E which, when subjected to zinc dust in the presence of acetone, afford ylide 2-F, and thence provides tetracyclic final product 2-H following treatment with piperidone 2-G and acid.

General Method B3.

Cyclization of o-hydroxy-aniline 3-A with an appropriately substituted dihaloalkane, such as 1,2-dibromoethane, yields benzoxazine 3-B. Nitrosation yields nitroso intermediate 3-C which, when heated with piperidone 3-D in acid produces the desired tetracyclic product 3-F. Alternatively, under similar conditions, the o-amino-thiophenol 3-F (or 2,2′-disulfanediyldianiline derivative) yields the intermediate benzothiazine 3-G and thence the thio analog 3-J. Alternatively, under similar conditions, the o-amino-aniline 3-K (R″═H, alkyl) yields the intermediate tetrahydroquinoxaline 3-L and thence the amino analog 3-N.

Use of alternative haloacetates, such as ethyl-2-bromoacetate in place of the dihaloalkanes, results in the acyl analog of the types 3-0 and 3-P. Use of α-substituted ethyl-2-bromoacetate reagents yields substituted analogs of the type 3-Q and 3-R. Compounds 3-S and 3-T can be prepared through reduction of the compounds 3-Q and 3-R, or intermediates thereto, respectively.

An alternative route commences by nucleophilic substitution of the orthohalonitrobenzene compound 3-U with an appropriately substituted nucleophilic alkyl halide 3-V followed by reduction of the nitro group to the amine 3-W. Conversion to the aryl hydrazine 3-X followed by Fischer-Indole reaction with piperidone 3-D as before gives the desired R′-substituted product 3-Y.

General Method B4.

Conversion of phenyl hydrazine 4-A to the intermediate ylide 4-B followed by cyclization yields the indole 4-C. Reduction of the indole 4-C to the indoline 4-D followed by nitrosation yields nitroso derivative 4-E which, after conversion to the successive ylide 4-F, yields the final tetracyclic product 4-H upon treatment with piperidone 4-G.

General Method B5.

Suzuki-coupling of bromoquinoline 5-A with an appropriately substituted boronic acid yields the aryl-coupled product 5-B. Reduction of 5-B to the tetrahydroquinoline 5-C followed by nitrosation gives the nitroso intermediate 5-D. Conversion of nitroso compound 5-D to the ylide 5-E, followed by heating with piperidone 5-F yields the final desired tetracycle 5-G.

General Method B6.

Appropriately substituted aryl hydrazine 6-A is treated with piperidone 6-B to produce the carboline tricycle 6-C. Base-mediated N-alkylation of 6-C with an appropriately substituted propene derivative results in the substituted allyl adduct 6-D. Allylation (n=11) at the bromo-substituted center of 6-D under Stille coupling conditions provides the allylated product 6-E. Finally, conversion to the cyclized tetracyclic azepino product 6-F is achieved under ring-closing metathesis (RCM) conditions involving catalysts known in the art, such as Grubbs “First Generation Catalyst”, “Second Generation Catalyst”, “Hoveyda-Grubbs Catalyst”, and the like. Reduction of 6-F under for example, hydrogenation conditions yields the saturated derivative 6-G. Alternatively, where n=0, vinylation of 6-D provides the vinylated version of 6-E, from which RCM results in the 6-membered analog of 6-F, with successive reduction producing saturated product 6-G.

General Method B7.

Treatment of appropriately substituted aryl hydrazine 7-A with piperidone 7-B results in the tricyclic carboline product 7-C. Palladium mediated amination of 7-C at the chloro-center, under Buchwald-Hartwig conditions, provides the aniline product 7-D. Reaction of 7-D with 2-chloroacetylchloride results in the tetracyclic piperazinone-type product 7-E.

General Method B8.

Treatment of appropriately substituted carboline 8-A with methylmagnesium chloride, followed by diethyl oxalate gave the ester intermediate 8-B which, following successive addition of the Grignard reagent R^aMgCl and/or R^bMgCl (or alternatively 2 equivalents of R^aMgCl) provides the tertiary alcohol product 8-C. Acid-mediated cyclization of 8-C affords the tetracyclic amide 8-D, from which reduction of the amide group under standard reductive conditions yields the amine final product 8-E.

General Method B9.

Treatment of appropriately substituted carboline 9-A with an α,β-unsaturated carbonyl compound such as acid chloride 9-B provides the amide 9-C. Lewis-acid-mediated cyclization of 9-C results in the tetracyclic product 9-D, whereupon reduction of which yields the final amine 9-E. Alternatively, treatment of 9-A with appropriately substituted acid chloride such as 9-F yields the amide 9-G, followed by cyclization to amide 9-H and reduction to the amine 9-J.

General Method B10.

The appropriately substituted indoline such as that from General Method 4,4-D, is converted to the N-carboxyethyl derivative 10-A. Base-mediated alkylation of 10-A leads to the alkylated product 10-B. Removal of the carboxymethyl group under basic conditions produces the secondary amine 10-C. Further conversion, following conditions analogous to those described in General Method 4, yields the desired tetracyclic product 10-G.

General Methods for the preparation of intermediate compounds to provide bicyclic analogs described herein are presented below in General Methods 11-13. Such bicyclic intermediates can be subjected to the conditions described in the Methods presented above.

General Method B11.

An appropriately substituted arylhydrazine 11-A is treated with alkyl halide 11-B to provide the N-alkylated product 11-C. Ring-closure of 11-C with acetal 11-D gives the 3-substituted indole 11-E which, upon heating with formaldehyde affords the tetracyclic product 11-F. The portion comprising R² and R⁴ can be converted to a ring during this route, using the Methods described above.

General Method B12.

Suitably substituted indole 12-A is reacted with maleimide 12-B to give 3-substituted derivative 12-C, followed by reduction with an appropriate reducing agent to generate substituted 3-(3-pyrrolidinyl)indole 12-D. This 3-(3-pyrrolidinyl)indole 12-D can then be reacted with formaldehyde, under standard Pictet Spingler reaction conditions (U.S. Pat. No. 2,642,438) to give the bicyclo-β-carboline 12-E. This β-carboline can then be functionalized to give cyclic product 12-F in an analogous manner to those steps provided for in the other General Methods described above.

General Method B13.

General Method 13 includes the use of Fischer-Indole conditions, well known to those in the art, whereby an appropriately substituted aryl hydrazine 13-A is condensed with various ketones, as exemplified by 13-B-13-D, to form aryl hydrazones, which are heated in dilute acid to complete the cyclization and provide the carboline products 13-E-13-G, respectively. If necessary any isomers can be separated at this stage, or after later steps. The carbolines can then be substituted at the NH position and/or at R⁴ using the conditions described in the General Methods above. The synthesis of the bicyclic ketone intermediates has been described by Bastable et al. [J. Chem. Soc. Perkin I (1981), 1346-1351]; King et al. [J. Med. Chem. (1993), 36:683-689]; and Mewshaw et al. [J. Med. Chem. (1993), 36:343-352], the experimental details therein are hereby incorporated by reference.

General Method B14

Preparation of N-Methyl and N-Ethyl 9-Chloro-1,2,3,4,5,6-hexhydroazepino[4,3-b]indole

A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent: EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%).

A mixture of 3-(4-chloro-2-iodo-phenylamino)-cyclohex-2-enone (0.5 g, 1.44 mmol), cuprous iodide (27.4 mg, 0.14 mmol), L-proline (33.12 mg, 0.29 mmol) and potassium hydroxide (0.32 g, 5.70 mmol) in DMSO (6 mL) were heated to 90° C. for 24 h. The reaction was cooled and poured into water. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (25 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a dark brown solid. This was recrystallized using acetonitrile water to give a brown solid (0.17 g, 54%). mp 281-282° C.

A solution of 6-chloro-2,3-dihydro-1H-carbazol-4(9H)-one (500 mg, 2.27 mmol), hydroxylamine hydrochloride (238 mg, 3.41 mmol) and NaOAc (280 mg, 3.41 mmol) in EtOH:water (4.5:2 mL) was heated to reflux (125° C.) for 5 h. The reaction mixture was concentrated to dryness. Water was added to the residue and the solid filtered, dried under vacuum to yield the title compound.

6-Chloro-2,3-dihydro-1H-carbazol-4(9H)-one oxime (4.39 g, 18.71 mMol) and polyphosphoric acid (119 g) was heated together at 120° C. for 20 min. After cooling to RT, ice-water mixture was added to hydrolyze the mixture and stirred for 2 h. The mixture was filtered and washed with NH₄OH (40 ml) followed by water. The resultant solid was dissolved in MeOH and filtered. The methanolic solution was concentrated to yield 4.7 g of crude as a brown solid. The crude product was purified by flash column chromatography over silica-gel (230-400 mesh) using EtOAc/Hexane followed by MeOH/EtOAc, the product eluting at 2-10% MeOH/EA.

Yield: 2.1 g (47.8%).

To an ice-cooled stirred suspension of Lithiumaluminum hydride (486 mg, 12.8 mmol) in dry THF (29 mL) was added dropwise a solution of 9-chloro-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (380 mg, 1.62 mmol) in dry THF (20 mL), and the reaction mixture heated to reflux for 15 h (89° C.). The reaction mixture was cooled to RT, quenched with water (3 mL), and 15% NaOH solution (6 mL) and water (9 mL), and then diluted with THF. The reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to yield the title compound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360 mg, 1.6 mmol) in THF (1 mL) was added dropwise to ethyl formate (1 mL). The reaction mixture was stirred at RT for 30 min, followed by heating to reflux for 14 h. The solvent was removed under reduced pressure to yield the title compound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360 mg, 1.6 mmol) was stirred in acetic anhydride for 12 h. The solvent was removed under reduced pressure to yield the title compound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (12.3 g, 55.9 mmol) in ethylformate (369 mL) was stirred at 55° C. for 2 h. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the crude product (13.5 g) was used for the next step without purification. To a stirred suspension of lithiumaluminum hydride (4.13 g, 108.8 mmol) in dry THF (405 mL) was added portionwise 9-chloro-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (13.5 g) and the mixture heated to reflux for 2 h. The progress of reaction was monitored by TLC. The reaction was quenched with saturated aqueous sodium sulfate solution at 0° C., and the mixture filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was washed with diethyl ether to yield the title compound (9.7 g). ¹H NMR (DMSO) δ (ppm): 11.02 (s, 1H, D₂O exchangeable), 7.45 (s, 1H), 7.25-7.22 (d, 1H), 6.98-6.95 (d, 1H), 3.72 (s, 2H), 2.90-2.80 (m, 4H), 2.30 (s, 3H), 1.82-1.77 (m, 2H).

To an ice-cooled stirred suspension of lithiumaluminum hydride (390 mg, 10.09 mmol) in 1,4-dioxane (15 mL) was added portionwise 1-(9-chloro-4,5-dihydroazepino[4,3-b]indol-2(1H,3H,6H)-yl)ethanone (300 mg, 1.14 mmol), and the reaction mixture heated to reflux for 6 h. The reaction mixture was quenched with water (1 mL), 15% aq. NaOH solution (3 mL) and water (3 mL), and extracted with warm EtOAc (3×50 mL). The combined organic extract was concentrated and the residue purified by silica gel (230-400 mesh) flash column chromatography (100% EtOAc) to yield the title compound (115 mg).

General Method B15

Preparation of 2,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole

To a solution of p-tolylhydrazine hydrochloride (7.5 g, 47.2 mmol) in 1,4-dioxane:conc. H₂SO₄ (225:16.5 mL) was added cyclohexane-1,3-dione (4.42 g, 39.4 mmol), and the mixture heated to reflux for 16 h (85-90° C.). The reaction mixture was cooled to RT, basified with 15% aqueous KOH (pH 10) and extracted with EtOAc. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound (7.7 g, crude).

A solution of 2,3-dihydro-6-methyl-1H-carbazol-4(9H)-one (5.8 g, 19.1 mmol), hydroxylamine hydrochloride (3.0 g, 43.6 mmol) and NaOAc (3.58 g, 43.6 mmol) in EtOH:water (58:25.3 mL) was heated to reflux (125° C.) for 5 h. The reaction mixture was concentrated to dryness. Water was added to the residue and the solid filtered, dried under vacuum to yield title compound.

To a preheated (105° C.) solution of polyphosphoric acid (225 g) was added powdered 6-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime (10 g) under nitrogen and heating continued for 15 min. The reaction mixture was cooled and to it was added crushed ice water. The crystallized solid obtained was collected by filtration. The solid was washed with water and then by dilute ammonium hydroxide, then dried under vacuum to obtain the desired product (8 g, crude product).

Lithiumaluminum hydride (3 g, 78.95 mmol) was placed in 1,4-dioxane (100 mL) under inert atmosphere and 9-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (3 g, 14.018 mmol) was added, and the mixture heated to reflux for 15 h. The reaction was monitored by TLC. The reaction was quenched with saturated aqueous sodium sulfate at 0° C., and the reaction mixture filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to afford solid, which was washed with water followed by EtOAc, and dried to afford 1.25 g of the title compound.

9-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (0.25 g, 1.25 mmol) was taken in ethylformate (18 mL, 227 mmol) and stirred at 55° C. for 3 h. The reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and used for the next step without purification (0.2 g).

To a stirred suspension of lithiumaluminum hydride (2 g, 52.63 mmol) in dry THF (150 mL) was added portionwise 9-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (5.9 g, 25.87 mmol) and the reaction mixture stirred at 55° C. for 2 h. The progress of reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium aqueous sulfate solution at 0° C. and then filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to afford the title compound (5.2 g). ¹H NMR (DMSO) 6 (ppm): 7.12-7.05 (m, 2H), 6.80-6.6.76 (d, 1H), 3.65 (s, 2H), 2.90-2.80 (m, 4H), 2.34 (s, 3H), 2.26 (s, 3H), 1.80-1.72 (m, 2H).

General Method C1

Treatment of appropriately substituted dimethylpiperidone 1-A with bases such as sodium hydride followed by addition of electrophile 1-B provides the alkylated product 1-C which, after heating with appropriately substituted hydrazine 1-D in the presence of acid provides the cyclized carboline product 1-E.

General Method C2

Treatment of appropriately substituted hydrazine 2-A with base and electrophile 2-B yields alkylated hydrazine product 2-C which, after heating with acid and appropriately substituted piperidone 2-D provides the cyclized carboline product 2-E.

General Method C3

Substituted piperidones of the type exemplified as compound 2-D in General Method 2 can be prepared through a number of means known to those skilled in the art. Common utilized conditions comprise a base-mediated treatment of compound 3-A with an electrophile such as R—X to produce the α-substituted product 3-B, which would be utilized as described in General Methods 1 and 2 to prepare compounds of the type 3-C. R can also be aromatic, wherein conditions can comprise palladium-mediated coupling reagents. Alternative electrophiles could include, for example, aldehydes, esters, carbonates, anhydrides, and the like.

Compounds of formulae (A1)-(A4), (A1a-A1r), (A3a)-(A3h), and variations thereof, are exemplified in Table 1 as compounds A1-A160. Compounds of formulae (B1)-(B4), (B1a)-(B1bm), (B3a-B3d), and variations thereof, are exemplified in Table 2 as compounds B1-B242. Compounds of formulae (C1)-(C4), (C1-a)-(C1r), (C3a)-(C3h), and variations thereof, are exemplified in Table 3 as compounds C1-C136. Compounds of formulae (D1)-(D4), (D1a)-(D1bm), (D3a)-(D3d), and variations thereof, are exemplified in Table 4 as compounds D1-D266.

The following Examples are provided to illustrate but not to limit the invention.

EXAMPLES

Example B1

Determination of the Ability of Compounds of the Invention to Bind an Adrenergic Receptor

Adrenergic α_2B

To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α_2B receptor expressed in Chinese hamster ovary (CHO) K1 cells (Uhlen, S. et al, Eur. J. Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA) was used. Compounds of the invention were incubated with 2.5 nM [3H]Rauwolscine for 60 min at 25° C. Non-specific binding was estimated in the presence of 10 μM Prazosin. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Rauwolscine specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Tables B1A-B1D.

Adrenergic α_2A

To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α_2A receptor expressed in insect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271:1558, 1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2 mM EDTA) was used. Compounds of invention were incubated with 1 nM [³H]MK-912 for 60 min at 25° C. MK912 was (2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-one hydrochloride Non-specific binding was estimated in the presence of 10 μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride). Receptor proteins were filtered and washed, the filters were then counted to determine [³H]MK-912 specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Tables B1A-B1D.

Adrenergic α_1B

To evaluate in radioligand binding assays the activity of compounds of the invention, rat adrenergic α_1B receptor obtained from Wistar Rat liver (Garcia-S'ainz, J. et al, Biochem. Biophys. Res. Commun. 186:760, 1992; Michel, A. et al, Br. J. Pharmacol. 98:883, 1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used. Compounds of the invention were incubated with 0.25 nM [³H]Prazosin for 60 min at 25° C. Non-specific binding was estimated in the presence of 10 μM phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [³H]Prazosin specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention were tested in this biochemical assay and percent inhibition of specific binding was determined. Biochemical assay results are presented as the percent inhibition of specific binding in Tables B1A-B1D.

Adrenergic α_1D

To evaluate in radioligand binding assays the activity of compounds of the invention, human recombinant adrenergic α_1D receptor expressed in human embryonic kidney (HEK-293) cells (Kenny, B. et al, Br. J. Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, was used. Compounds were incubated with 0.6 nM [3H]Prazosin for 60 min at 25° C. Non-specific binding was estimated in the presence of 10 μM phentolamine. Receptor proteins were filtered and washed, the filters were then counted to determine [3H]Prazosin specifically bound. Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assay results are presented as the percent inhibition of specific binding in Tables B1A-B1D.

TABLE B1A
Percentage inhibition of ligand binding to aminergic G protein-
coupled receptors by compounds of the invention:
		Adrenergic
Compound	Adrenergic (0.1 μM)	(0.03 μM)
No.	α1B	α2A	α2B	α1D	α2B
A7	2	10	−9	4	—
A8	−3	20	−1	3	—
A9	−9	0	−7	−1	—
A10	11	23	8	26	—
A11	−1	4	14	−1	—
A12	2	−4	6	38	—
A13	−9	−12	5	8	—
A14	0	12	−3	−9	—
A15	0	20	21	5	—
A16	1	31	17	−2	—
A17	9	14	21	−5	—
A18	30	6	38	34	—
A43	−1	7	—	—	26
A44	−3	−5	—	—	31

TABLE B1B
Percentage inhibition of ligand binding to aminergic
G protein-coupled receptors by compounds of the invention:
	Adrenergic
Compound	(1 μM)	Adrenergic (0.1 μM)
No.	α1D	α2A	α2B	α1B	α2A	α2B	α1D
B1	28	15	47	—	—	—	—
B2	24	89	74	—	—	—	—
B3	38	89	68	—	—	—	—
B12		—	—	28	75	72	28
B160		—	—	2	−1	−8	15
B161		—	—	2	13	7	1
B162		—	—	−6	14	27	−2
B163		—	—	6	5	4	15
B164		—	—	12	6	16	2
B165		—	—	0	40	43	0
B210		—	—	—	—	14	—
B211		—	—	—	—	82	—

TABLE B1C
Percentage inhibition of ligand binding to aminergic G protein-
coupled receptors by compounds of the invention:
	Adrenergic (0.1 μM)
	Compound No.	α1B	α2A	α2B	α1D
	C47	34	15	32	10
	C48	20	2	−12	13

TABLE B1D
Percentage inhibition of ligand binding to aminergic G protein-
coupled receptors by compounds of the invention:
	Adrenergic (0.1 μM)
	Compound No.	α1B	α2A	α2B	α1D
	D10	−3	−1	−6	−6
	D11	16	8	30	−5
	D12	10	5	−7	−3

Example B2

Functional Activity on Recombinant Adrenergic α_1B, Adrenergic α_2A Adrenergic α_2B and Adrenergic α_1D Receptors Using Aequorin and GTPγS Functional Assays

To study the functional activity of compounds of the invention on the human recombinant adrenergic α_2B, adrenergic α_2A, adrenergic α_1B or adrenergic α_1D with Aequorin functional assays and on the human recombinant adrenergic α_2B receptor with GTPγS assay, CHO-K1 cell lines expressing adrenergic α_2B, adrenergic α_2A, adrenergic α_1B or adrenergic α_1D recombinant receptor, mitochondrial apoaequorin and Gα16 are used for the Aequorin assay. CHO-K1 cell line expressing the recombinant α_2B receptor is amplified to prepare membranes used for the GTPγS assay.

The following reference agonists are used as both the reference ligand in agonist mode and as the agonist that needs to be inhibited in antagonist mode.

					α2B
Assay	α1B (aeq)	α1D (aeq)	α2A (aeq)	α2B (aeq)	(GTPgS)
Agonist	Cirazoline	Cirazoline	UK 14304	Oxyme-	Guanfacine
ligand				tazoline

Aequorin Assay Procedure:

Aequorin adrenergic α_1B (FAST-008A), adrenergic α_2A (FAST-006A) or adrenergic α_2B (FAST-007A) cells are grown 18 h prior to the test in media without antibiotics. They are then detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and re-suspended in “assay buffer” (DMEM/HAM's F12 with HEPES+0.1% BSA protease free). Cells are incubated at RT for at least 4 h with Coelenterazine h (Molecular Probes). Dose response curves with reference compounds are performed before testing the compounds of the invention. The α_1B reference agonist and antagonist are cirazoline and qinazoline, respectively. The α_2A reference agonist and antagonist are UK14,304 and rauwolscine, respectively. The α_2B reference agonist and antagonist are oxymetazoline and rauwolscine, respectively.

For agonist testing, 50 μL of cell suspension are injected on 50 μL of test compound or reference agonist plated in a 96-well plate. The resulting emission of light is recorded using the Hamamatsu Functional Drug Screening System 6000 (FDSS 6000). For antagonist testing, following an incubation of 15 min. after the first injection, 100 μL of reference agonist at a concentration corresponding to its EC₈₀ is injected on the 100 μL of the mixture of cell suspension and test compound. The resulting emission of light is recorded using the same luminometer as for agonist testing. To standardize the emission of recorded light (determination of the “100% signal”) across plates and across different experiments, some of the wells contained 100 μM digitonin or a saturating concentration of ATP (20 μM). Plates also contained the reference agonist at a concentration equivalent to the EC₈₀ obtained during the test validation.

Agonist activity of test compound is expressed as a percentage of the activity of the reference agonist at its EC₁₀₀ concentration. Antagonist activity of test compound is expressed as a percentage of the inhibition of reference agonist activity at its EC₈₀ concentration.

Test compounds are tested for agonist & antagonist activity at the human adrenergic α_1B (FAST-008A), adrenergic α_2A (FAST-006A) or adrenergic α_2B (FAST-007A) at the following nanomolar concentrations, in duplicate: Agonist (nM): 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000; Antagonist (nM): 0.15, 0.5, 1.5, 5, 15, 50, 150, 500, 1500, 5000.

GTPγS Assay Procedure:

The procedure is carried out with the following: assay buffer [20 mM HEPES pH 7.4; 100 mM NaCl, 10 μg/mL saponin, 1 mM MgCl₂]; membranes [Recombinant CHO-K1-adrenergic α_2B membrane extracts thawed on ice and diluted in assay buffer to give 10 μg/well and kept on ice]; GDP [diluted in assay buffer to give 3 M final concentration]; beads [PVT-WGA (Amersham, RPNQ0001), diluted in assay buffer at 0.5 mg/well]; GTPγ³⁵S [(PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nM final concentration]; ligand [Guanfacine (Tocris, 1030) as reference agonist and Rauwolscine (Tocris, 891) as reference antagonist, diluted in assay buffer]. Membranes are mixed with GDP (volume:volume) and incubated for at least 15 min. on ice. In parallel, GTPγ[³⁵S] is mixed with the beads (volume:volume) just before starting the reaction.

For agonist testing, the following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 μL of test or reference ligand, 20 μL of the membranes:GDP mix, 10 μL of assay buffer and 20 μL of the GTPγ[³⁵S]:beads mix. For antagonist testing, the following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 μL of test or reference ligand, 20 μL of the membranes:GDP mix, and then after an incubation of 15 min. at RT, 10 μL of reference ligand at historical EC₈₀ concentration and 20 L of the GTPγ[³⁵S]:beads mix.

The plates are covered with a top seal, mixed on an orbital shaker for 2 min, and then incubated for 1 h at RT. Then the plates are centrifuged for 10 min. at 2000 rpm, incubated at RT 4 h and counted for 1 min/well with a Perkin Elmer TopCount reader.

Test compounds are tested for antagonist activity at the human adrenergic α_2B receptor (FAST-007G) (FIG. 4) at the following nanomolar concentrations, in duplicate: Agonist and antagonist (nM): 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000.

Inverse Agonist Activity

SPA 35S-GTPgS and Radioligand Binding experiments are conducted with Euroscreen membrane preparations. Test compound is tested for inverse agonist activity at the human Adrenergic a2A receptor using GTPg35S binding functional assay (FAST-006G) in dose-response and in duplicates.

Example B3

Cell Culture and Cell Viability Assay

SH-SY5Y cells cultured in DMEM/F12 media supplemented with 10% FBS were seeded in 96-well microplates at 150,000 cells/cm². After 24 h, cells were depleted from FBS and kept in culture for 24 h before the experiment. A stock solution was prepared by dissolving the calcium ionophore 4-Br-A23187 (Calbiochem Cat. N^o 100107) in DMSO at 25 mM. Cells were then treated with 4-Br-A23187 (2 μM), hydrogen peroxide (300 μM) or the mitochondrial toxin rotenone (25 μM) in the presence of vehicle or Compound of the Invention for 24 h. Cell death was determined by measurements of LDH release according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany). Cell viability was determined by measuring the capacity of cells to metabolize MTS tetrazolium (MTS) according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany) and MTS reduction was assessed by the CellTiter 96® AQueous One Solution Cell Proliferation assay (Promega Corporation, Madison, Wis., USA). Compounds were screened at 10 nM, using DMSO as vehicle. Assay results for the experiments with Br-A23187 were presented as the MTS reduction capacity (cell viability) of untreated cells (control), 4-Br-A23187-treated cells (vehicle), and co-incubation of Br-A23187 with Compounds of the Invention treated cells and using p-trifluoromethoxyphenylhydrazone (FCCP) at 10 μM for 30 min as a control. This assay assesses the ability of the test compounds to protect against cell death that was mediated by mitochondrial dysfunction. In the assay, the calcium ionophore 4-Br-A23187 was used to challenge the cells, causing calcium levels to rise in mitochondria, which leads to depolarization and cell death. Test compounds were assessed for their ability to prevent cell death in response to challenge with 4-Br-A23187.

TABLE B3
Relative Cytoprotection efficiency of compounds of the invention
		Relative
		Cytoprotective
	Compound No.	capacity	SE	p value
	Control	100	1.47E−06	—
	Vehicle	0	0	—
	A1	−1.10264	48.94656	ns
	A2	−4.4068	30.13848	ns
	A3	35.08263	11.90545	ns
	A5	28.81883	6.21819	0.0435
	A6	27.59688	3.322046	0.0142
	A9	15.84906	12.76087	ns
	A11	37.63225	18.00517	ns
	A12	35.74884	18.90774	ns
	A13	19.74211	12.6988	ns
	A17	10.7958	19.56162	ns
	A18	26.00401	19.9292	ns
	C43	9.618124	27.03942	ns
	C44	−0.63416	27.95942	ns
	C45	4.347974	27.88415	ns
	C46	−0.04527	28.24442	ns
	C48	52.14072	23.16085	ns
	D2	38.36419	24.02967	ns
	D5	72.11077	1.524916	4.00E−04
	D7	72.05842	8.628121	0.014
	D8	73.11748	10.89231	0.0215
	D9	81.05257	2.423629	9.00E−04
	D11	30.32596	2.105927	0.0048
	D12	32.51647	14.49203	ns

Example B4

Cell Culture and Cell Viability Assay

Cell Culture.

SH-SY5Y cells stably transfected with a doxycyline (dox)-inducible wild-type α-synuclein (α-syn) gene along with control SH-SY5Y cells over-expressing the β-galactosidase (β-gal) gene (a gift from L. Stefanis, Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece) are cultured as described by Vekrellis et al. (Vekrellis K, Xilouri M, Emmanouilidou E, Stefanis L. (2009). Inducible over-expression of α-syn in human neuronal cells leads to caspase-dependent non-apoptotic death. J Neurochem 109, 1348-1362). In accordance with this method, cells are cultured and maintained in RPMI 1640, 10% fetal bovine serum supplemented with 250 μg/mL G418 and 50 μg/mL Hygromycin B. Expression of α-syn is switched off in stock cultures with doxycycline (2 μg/mL). For experimental procedures, cells are plated at (4-8×10⁴ cells/cm²) and differentiated in absence of doxycycline and in the presence of 20 μM all-trans retinoic acid (RA) (Sigma, St Louis, Mo., USA).

Viability Assay:

Cells are cultured in 96-well plates. After 24 h, cells are treated with RA and Compounds of Invention at 0.1 and 10 nM in the absence of doxycyline. Culture medium with RA and drugs is fully replaced after 7 days. Cell viability is measured by the release of lactate dehydrogenase (LDH) from necrotic cells into the culture medium and by measuring the capacity of cells to metabolize MTS tetrazolium (MTS) after 14 days in culture. LDH leakage is assessed according to the Cytotoxicity Detection KitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by the CellTiter 96® AQueous One Solution Cell Proliferation assay (Promega Corporation, Madison, Wis., USA).

Assay results for the experiments with α-syn over-expression are presented as the MTS reduction capacity (cell viability) of control cells (+dox), cells over-expressing α-syn (-dox), and cells over-expressing α-syn incubated with Compounds of the Invention at 0.1 nM or 10 nM.

Immunoblotting of α-Synuclein and α-Synuclein Aggregates:

Cells stably expressing α-synuclein are cultured in 6-well plates at a density of 4×10⁴ cells/cm² cells per well. Cells are differentiated and treated with Compound of the Invention at 10 nM in absence of dox after 24 h of plating. Drug treatments are repeated after 7 days in freshly prepared medium containing RA. After 14 days, cells are washed twice with cold PBS and lysed in lysis buffer containing 1% Triton X-100, 20 mM HEPES, 150 mM NaCl, 10% glycerol, 1 mM EGTA, 1.5 mM MgCl₂, 1 mM PMSF pH 7.4, and 1× protease inhibitor mixture (Roche, Mannheim, Germany). Lysates are homogenized and subjected to four successive freeze-thaw cycles to disrupt membranes. Triton soluble fractions and triton insoluble pellets are obtained by ultracentrifugation at 100,000×g for 30 min at 4° C. The concentration of protein in each fraction is determined by BCA assay (Thermo Scientific). Samples from total, soluble and triton insoluble fractions, are boiled in 1× sample buffer (20 mM Tris, 1% glycerol, 180 mM (3-mercaptoethanol, 0.003% bromophenol blue, and 2% SDS, pH 6.8), loaded on 12% SDS-PAGE gels, and transferred to polyvinylidene difluoride (PVDF) membranes (0.2 μM-pore immobilon Biorad). Membranes are blocked in 1×TBS-Tween (20 mM Tris, pH 7.4, 150 mM NaCl, and 0.2% Tween 20) containing 5% milk for 1 h and incubated overnight at 4° C. with the following primary antibodies in blocking solution at the indicated dilutions: monoclonal anti-α-synuclein α-syn-1 (1:1000; BD Transduction Laboratories). (Perrin, R. J., Payton, J. E., Barnett, D. H., Wraight, C. L., Woods, W. S., Ye, L., and George, J. M. (2003). Epitope mapping and specificity of the anti-α-synuclein monoclonal antibody Syn-1 in mouse brain and cultured cell lines. Neurosci Lett 349, 133-135), and monoclonal vimentin (1:1000; BD PharMingen). Primary antibodies are detected with secondary anti-mouse antibodies conjugated to HRP (1:5000).

Isolation of RNA and RT-Quantitative PCR(RT-qPCR):

SH-SY5Y cells stably over-expressing α-syn are treated with Compound of the Invention (10 nM). Total RNA from these cells as well as control cells not treated with Compound is extracted using the E.Z.N.A RNA extraction Kit (OMEGAbiotek, Norcross, Ga.). 1 μg of RNA is reverse transcribed to cDNA using the M-Mulv reverse transcriptase enzyme (Promega Corporation, Madison, Wis., USA). RT-qPCR of cDNA templates is carried out using TAQMAN probes for human α-synuclein (Hs00240906_M1) and TAQMAN masterMix (Applied Biosystems) and a Mx3005P real-time PCR system (Agilent Technologies Inc., Santa Clara, Calif.). Levels of alpha-tubulin mRNA are used to normalize the amounts of total RNA between samples. Fold changes are calculated as described by (Pfaffl, M. W. (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29, e45).

Example B5

α_2B Pharmacology: Studies in Spontaneously Hypertensive Rat (SHR) Model of Hypertension

Male spontaneously hypertensive rats (SHR), approximately 3 months of age and weighting approximately 250 grams are utilized. Free access to standard lab chow for rats and reverse osmosis (RO) water is granted. All aspects of this work, including housing, experimentation and disposal of animals are performed in general accordance with the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996).

The animals are anaesthetized with sodium pentobarbital (50 mg/kg IP). The left carotid artery when compound dosed orally (PO) or subcutaneously (SC); and both left carotid and femoral artery when compound dosed intravenous (i.v.) are cannulated with a polyethylene catheter (38 cm in length; PE60, Portex, Ltd.) connected with a polyurethane tubing (12 cm in length; PU-40, Cat. #BB520-40, Scientific Commodities, Inc.), which is tunneled under the skin and exited through the nape of the neck. The arterial cannula is connected to a pressure transducer through a swivel system, allowing free roaming during continuous recording of mean arterial pressure and heart rate. The animals are housed individually with food and water freely available during recovery. On the following day, the arterial cannula is connected via a Statham (P 23×L) pressure transducer to a NEC/San-Ei amplifier and data acquisition and analysis system (Power Lab 8/SP) for direct mean arterial pressure and heart rate measurements.

The test compounds, dissolved in sterile saline, are administered subcutaneously (SC) or orally (PO), or by intravenous (i.v.) bolus administration in two minutes or the escalating doses of compound administration in every 30 minutes, with each dose and its strength delivered over 2 minutes as shown in the respective figures; the internal standard phentolamine is given by oral gavage. The control group received vehicle alone. Immediately before (−10 min and −5 min) and at 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 3.5 hr, and 4 hr post-dosing, systolic pressure blood pressure values are recorded. Effect of the test compounds on blood pressure is determined.

Example B6

α_2B Pharmacology: Studies in Healthy Dogs and Dexmedetomidine (DEX) Induced Beagle Dog Model of Hypertension

These studies are conducted in both acute and chronic modes.

Four adult beagle dogs of both sex and weighted around 10 kg are chosen for the acute studies after a preliminary qualitative electrocardiogram/ECG, clinical pathology and physical examination. Upon arrival at the laboratory, the dogs are weighed and acclimated for a period of one week. Lab Diet certified canine diet #5007, PMI Nutrition International Inc is made available ad libitum to all dogs except during fasting periods. The dogs are surgically implanted with a pressure transducer equipped telemetry transmitter under sodium pentobarbitone anesthesia. The transmitter assembly is secured internally and the fluid-filled catheter is placed into an appropriate artery.

In the acute studies, the test compounds at different doses is administered by oral gavage, 30 minutes prior to intravenous dexmedetomidine (5 μg/kg) challenge. Dexmedetomidine administration is enabled by prior placement of a peripheral intravenous line. The same four dogs are received all four treatments in the order noted in the table below, with at least a 3-day washout period between treatments.

In another acute study, the test agent is administered a dose of 6 mg/kg by oral gavage to 4 healthy dogs; and the blood pressure monitored for a period of 4 hours.

For the chronic study mode (see Table B9), the test compound at 3 doses is administered by oral gavage once on day 1 and then twice/day on days 2 to 14, and finally once on day 15. The dexmedetomidine is administered on day −4 to check its effectiveness in inducing blood pressure, and once following the morning dose of test compound or vehicle on days 2, 7 and 14. Blood pressure and heart rate data are collected 1 h prior & 4 h post-morning dose on days 1, 2, 7, 14 and 15 to allow the appropriate data comparisons. Blood aliquots are saved at 4 h post-morning dose for exposure determination.

TABLE B9
Chronic dosing sequence and study design for test compound
Test compound - 30 minute
Pretreatment (mg/kg, p.o.) with	Dexmedetomidine	Number of
b.i.d. regimen for 14 days	Challenge (μg/kg, i.v.)	Dogs
0	5	6
6	5	6
18	5	6
	Day
	−4	1	2	7	14	15
Compound	—	am	am/pm	from day 2	to day 14	Am
dosed on				am/pm	am/pm
DEX*	Am	—	Am	am	Am	—
*DEX administered 30 min following am dose of test compound.

In both acute and chronic studies, dogs are weighed before dosing. Cardiovascular evaluations at each dose of test compound are collected with animals gently restrained in a sling. Dogs are placed in the sling at least 1 hour prior to dose administration, and after at least 30 minutes of stable baseline data collection. The dogs are monitored continuously for 3-4 hours subsequent to test compound administration and summarized in 5-minute bins. The systolic blood pressure is collected. Data is reported as mean±SEM or mean.

In acute studies, oral administration of test compound dose-dependently reduced systolic blood pressure in both healthy and dexmedetomidine induced dogs that are tested in the acute mode.

Adrenergic receptors α_2B and α_2A mixed inhibitor's pharmacology—Studies in Spontaneously Hypertensive Rat (SHR) Model of Hypertension: Similar to dosing regimen for selective antagonists of adrenergic receptor α_2B, the mixed inhibitors is dosed orally (PO) or intravenous (i.v bolus or escalating doses) to SHR rats. A compound that is an adrenergic receptor α_2B antagonist also showing adrenergic receptor α_2A antagonist and/or inverse agonist activity can be useful for reducing blood pressure in an individual with hypertension who is also suffering from metabolic syndrome.

Example B7

Peripheral and Central Effects of Test Compound on Blood Pressure in Conscious Rabbits

Four adult New Zealand White rabbits of both sexes are chosen for these studies. The experiments are conducted in accordance with the Australian code of Practice for the Care and use of Animals for Scientific Purposes and approval is sought from the Animal Experimental Committee of Alfred Hospital, Baker IDI, Melbourne, Australia. The conscious rabbits are implanted with an intravenous catheter in marginal ear vein or by centrally by intracisternal catheter interfaced to a pressure transducer connected to a suitable recorder. To unveil peripheral effects of test compound, two sets of acute studies are conducted in rabbits. In the first set of studies, test compound is dosed to rabbit intravenously for a dose-response study with cumulative doses starting 0 (Ringer's Lock solution as a vehicle), 0.1, 0.3, 1, 3.2 and 10 mg/kg where each dose is tested on a separate day. A single intravenous bolus dose at 3 mg/kg is given and a time-course study is conducted in the second set of studies. Systolic, diastolic, mean and diastolic blood pressures are recorded in both the studies. Data collections are made for 3 hours in the second set of studies. Heart rate (HR) is derived electronically using an algorithm to determine HR from pulse interval. In a separate set of studies, Clonidine (positive control) is tested where all experimental procedures including dose-regimen are identical to that of the studies with test compound.

The mean arterial pressure responses to test compound are dose-dependent in the dose-response study with cumulative doses Under similar conditions, Clonidine produces a maximum drop of arterial blood pressure of −6 mmHg before the blood pressure reversed back.

The cardiovascular effects of intracranial administration of test compound are tested in rabbits. Test compound is administered by infusion directly into the brain with the cannula delivering the compound placed directly into the 4th ventrical of the brain. Several doses are tested for cardiovascular effects, including effects on blood pressure and heart rate, following direct brain infusion. The blood pressure effects following intravenous and ventricular infusion provides the effect of the compound on the peripheral and central nervous systems respectively.

Example B8

Renal Effects of Test Compound in Conscious Rabbits

The long duration of blood pressure effect of a test compounds of the invention results in a reduction in blood volume that can result from diueresis and/or the movement of fluid from the vascular space to the extravascular space. The effect of test compound on hematocrit levels is measured, compounds that reduce blood volume increase hematocrit. Characterization of the effect of α_2B antagonists on renal function is determined by measuring urine volume, urine sodium and urine potassium using methods described by Burke et al. (Effects of chronic sympatho-inhibition on renal excretory function in renovascular hypertension Sandra L. Burke, Roger G. Evans and Geoffrey A. Head. Journal of Hypertens 29:945-952 (2011).

Example B9

Human Clinical Studies

The compound is studied in a clinical trial of hypertensive patients who have not reached their blood pressure goals on current therapy. The target patient population are patients with refractory hypertension that have not reached their blood pressure goals despite use of at least 3 different blood pressure agents. The study compares the active compound against a matched placebo compound with the primary objective of comparing mean blood pressure change from baseline to the end of the study between the active compound and placebo.

All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1: A method of lowering blood pressure in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof:

wherein

wherein for formula (A1) or (A2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;

each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2 and X3 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (A3) or (A4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R5 is H or unsubstituted C1-C8 alkyl; each m, n, o and p is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (B1) or (B2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;

each m, n, or o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2 and X3 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (B3) or (B4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety; each m, n and o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d;

Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h:

Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond;

each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a are taken together to form a bond, or R7c and R7e, where present, are taken together to form a bond;

each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f, where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond;

each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and

R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (C1) or (C2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and a vicinal R8(a-h) are taken together to form a bond; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and a vicinal R8(a-h) are taken together to form a bond; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R2, where present, to form a bond,

or is taken together with vicinal R4, where present, to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (C3) or (C4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and a vicinal R8a, where present, are taken together to form a bond;

R5 is H or unsubstituted C1-C8 alkyl;

each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R4 to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety; Or

wherein for formula (D1) or (D2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and R7a are taken together to form a bond; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and R7a are taken together to form a bond; each m, n and o is independently 0 or 1; each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R2 are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (D3) or (D4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and R7a are taken together to form a bond; each m, n and o is independently 0 or 1; each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

2: The method of claim 1, wherein the individual has high blood pressure.

3: The method of claim 2, wherein the method reduces systolic blood pressure of the individual.

4: The method of claim 2, wherein the method reduces diastolic blood pressure of the individual.

5: The method of claim 2, wherein the method reduces (i) mean arterial blood pressure, or (ii) pulse pressure, of the individual.

6: The method of claim 3, wherein the method does not substantially increase heart rate of the individual.

7: The method of claim 1, wherein the individual has one or more risk factors for developing high blood pressure.

8: A method of (i) increasing renal blood flow, and/or (ii) decreasing sodium reabsorption, in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof:

wherein

wherein for formula (A1) or (A2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2 and X3 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (A3) or (A4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R5 is H or unsubstituted C1-C8 alkyl; each m, n, o and p is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (B1) or (B2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each m, n, or o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R79 are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2 and X3 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (B3) or (B4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety; each m, n and o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d;

Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h;

Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond;

each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a are taken together to form a bond, or R7c and R7e, where present, are taken together to form a bond;

each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f, where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond;

each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (C1) or (C2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and a vicinal R8(a-h) are taken together to form a bond; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and a vicinal R8(a-h) are taken together to form a bond; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R2, where present, to form a bond,

or is taken together with vicinal R4, where present, to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (C3) or (C4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and a vicinal R8a, where present, are taken together to form a bond;

R5 is H or unsubstituted C1-C8 alkyl;

each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R4 to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (D1) or (D2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and R7a are taken together to form a bond; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and R7a are taken together to form a bond;

each m, n and o is independently 0 or 1; each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R2 are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (D3) or (D4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and R7a are taken together to form a bond;

each m, n and o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

9: The method of claim 8, wherein the method results in increase in renal blood flow.

10: The method of claim 8, wherein the method results in decrease in sodium reabsorption.

11: The method of claim 9, wherein the method results in increase in urine sodium content and/or increase in urine volume.

12: The method of claim 9, wherein the method results in any one or more of: (i) reducing edema, (ii) reducing elevated blood urea nitrogen to creatinine (BUN/Cr) ratio, and (iii) decreasing creatinine levels.

13: The method of claim 1, wherein the individual has or is at risk of developing acute or chronic congestive heart failure, acute decompensated congestive heart failure, acute or chronic renal failure, or acute or chronic renal failure due to renal insufficiency.

14: A method of treating a disease or condition that is responsive to any one or more of: (i) a decrease in blood pressure; (ii) an increase in renal blood flow; and (iii) a decrease of sodium reabsorption, comprising administering to an individual in need thereof an effective amount of a compound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof:

wherein

wherein for formula (A1) or (A2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;

each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2 and X3 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (A3) or (A4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R5 is H or unsubstituted C1-C8 alkyl; each m, n, o and p is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (B1) or (B2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each m, n, or o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2 and X3 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (B3) or (B4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety; each m, n and o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d;

Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h;

Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond;

each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a are taken together to form a bond, or R7c and R7e, where present, are taken together to form a bond;

each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f, where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond;

each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and

R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (C1) or (C2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;

each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and a vicinal R8(a-h) are taken together to form a bond;

each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;

each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and a vicinal R8(a-h) are taken together to form a bond; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R2, where present, to form a bond,

or is taken together with vicinal R4, where present, to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (C3) or (C4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and a vicinal R8a, where present, are taken together to form a bond;

R5 is H or unsubstituted C1-C8 alkyl;

each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R4 to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (D1) or (D2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and R7a are taken together to form a bond; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and R7a are taken together to form a bond; each m, n and o is independently 0 or 1; each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f;

Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R2 are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (D3) or (D4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and R7a are taken together to form a bond; each m, n and o is independently 0 or 1; each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

15: The method of claim 14, wherein the disease or condition is hypertension.

16: The method of claim 15, wherein the disease or condition is treatment-resistant hypertension.

17: The method of claim 14, wherein the disease or condition is hypertensive emergency.

18: The method of claim 14, wherein the disease or condition is a cardiac or renal disease or condition.

19: The method of claim 1, wherein the compound is an adrenergic receptor α2B antagonist.

20: The method of claim 19, wherein the compound is also an adrenergic receptor α1B antagonist.

21: The method of claim 19, wherein the compound is also an adrenergic receptor α1D antagonist.

22: A kit comprising (i) a compound of formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof, and (ii) instructions for use according to the method of claim 1; and wherein

wherein

wherein for formula (A1) or (A2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2 and X3 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (A3) or (A4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R5 is H or unsubstituted C1-C8 alkyl; each m, n, o and p is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (B1) or (B2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each m, n, or o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2 and X3 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and

R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (B3) or (B4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b R3a, R3b, R4a, R4b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3, R4 or R10 to form a carbonyl moiety or a cycloalkyl moiety; each m, n and o is independently 0 or 1;

each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m, n and o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n and o are each 0, then R5a and R7c are taken together to form a bond, or

when m and n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m, n and o are each 1, then R5a and R79 are taken together to form a bond;

each m, n and o is independently 0 or 1;

each X1, X2 and X3 is independently N, CH or CR6;

Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d;

Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h;

Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond;

each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a are taken together to form a bond, or R7c and R7e, where present, are taken together to form a bond;

each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f, where present, are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond;

each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and

R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (C1) or (C2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and a vicinal R8(a-h) are taken together to form a bond; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and a vicinal R8(a-h) are taken together to form a bond; R5 is H or unsubstituted C1-C8 alkyl; each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R2, where present, to form a bond,

or is taken together with vicinal R4, where present, to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (C3) or (C4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and a vicinal R8a, where present, are taken together to form a bond;

R5 is H or unsubstituted C1-C8 alkyl;

each X1, X2, X3 and X4 is independently N, CH or CR6; each m, n, o and p is independently 0 or 1;

each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R8a, R8b, R8c, R8d, R8e, R8f, R8g and R8h, where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-aralkyl, substituted or unsubstituted amino, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety,

or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety,

or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety,

or is taken together with a vicinal R8(a-h) to form a bond provided when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl and thiol and thiol,

or is taken together with vicinal R4 to form a bond; and Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;

or

wherein for formula (D1) or (D2): R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R2a, where present, are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety or R1 and R4a, where present, are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each R2, R2a and R2b, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2 and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2 and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2 and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R2 and R7a are taken together to form a bond; each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; each R4 or R4a, where present, is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and R7a are taken together to form a bond; each m, n and o is independently 0 or 1; each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R2 are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond; each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond; each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

or

wherein for formula (D3) or (D4):

R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R2a, R2b, R3a, R3b, R10a and R10b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2, R3 or R10 to form a carbonyl moiety or a cycloalkyl moiety;

R4 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R4 and R7a are taken together to form a bond; each m, n and o is independently 0 or 1; each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R5a and R5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or

when m-o are each 0, then R5a and R7a are taken together to form a bond, or

when m is 1, and n-o are each 0, then R5a and R7c are taken together to form a bond, or

when m-n are each 1, and o is 0, then R5a and R7e are taken together to form a bond, or

when m-o are each 1, then R5a and R7g are taken together to form a bond;

each m, n and o is independently 0 or 1; each X1, X2, X3 and X4 is independently N, CH or CR6; Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2, where present, is CR7cR7d; Y2, where present, is CR7cR7d, NR8, O, S, S(O) or SO2, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3, where present, is CR7eR7f; Y3, where present, is CR7eR7f, NR8, O, S, S(O) or SO2, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4, where present, is CR7gR7h; Y4, where present, is CR7gR7h, NR8, O, S, S(O) or SO2, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f; each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R7c, where present, are taken together to form a bond, or R7a and R4 are taken together to form a bond; each R7c and R7d, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a, where present, are taken together to form a bond, or R7c and R7e are taken together to form a bond;

each R7e and R7f, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where present, are taken together to form a bond;

each R7g and R7h, where present, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond; and R8 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.